Sleep inducing compounds and methods relating thereto

ABSTRACT

Compounds having the following structure:  
                 
 
including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , L 1 , L 2  and n are as defined herein. Pharmaceutical compositions containing one or more compounds of structure (I), as well as methods relating to the use thereof, including methods for treating insomnia, inducing sleep or inducing sedation or hypnosis, are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 60/558,642 filed Apr. 1, 2004, whichapplication is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to sleep inducing compounds, as well asto methods for induction of sleep by administration of one or more ofsuch compounds to an animal in need thereof.

2. Description of the Prior Art

Most people experience, at least transiently and often chronically,problems with sleep. Insomnia occurs at all ages with half of all adultsin the United States affected at times (The Gallup Organization, Sleepin America: A National Survey of U.S. Adults, The National SleepFoundation, Washington, D.C., 1995). Insomnia compromises feelings ofwell-being and judgment and performance at tasks requiring alertness(Gillin, Postgrad Med. 1992; 92: 157-160). Significantly, inadequatesleep correlates with increased morbidity and mortality (Zammit et al,Sleep 1999;22: S379-85).

In a clinical setting, insomnia may be classified as transient,short-term, or chronic, with durations of a few days, a few weeks, orlong-term, respectively (Chessor, Sleep 2000;22: 237-41). Commonetiologies for transient insomnia include acute illness, social stress,jet lag, and work shift changes. Short-term insomnias can be caused bygrief, stress, and substance exposure. Chronic insomnias can beassociated with underlying disease, depression, psychophysiologicconditions, chronic stress, bereavement, substance exposure, and avariety of primary sleep disorders including sleep apnea, periodic limbmovement disorder, restless leg syndrome, narcolepsy and hypersomnia.The primary task of the physician is to identify the specific etiologyof the insomnia and prescribe a causally specific therapeuticintervention (Pary et al, Postgrad Med. 1996; 100: 195-210).

The categories of drugs used as sedative-hypnotics in the United States(Wang et al, Drug Disposition and Pharmacokinetics 2003; 37: 10-29)include barbiturates, the benzodiazepine hypnotics, benzodiazepinenonhypnotics, benzodiazepine receptor agonists, antidepressants,antipsychotics, miscellaneous compounds including chloral hydrate, andthe antihistamines.

With regard to the antihistamines, histamine enjoys a variety ofimportant chemical messenger roles, having activity toward at least fourhistamine receptors (i.e., H₁-H₄) and regulatory function in thenervous, gastrointestinal and immune systems. The antihistamines arereversible competitive ligands of the histamine H₁ receptor, and havebeen categorized over the years as first-, second-, or third-generationclasses differentiated by chemical structure and refinement of action.Specifically, first-generation antihistamines such as diphenhydramine,chlorpheniramine, clemastine, hydroxyzine and triprolidine provide H₁receptor blockade, but have significant side effects including sedation,CNS dysfunction due to leakage into the CNS, and anticholinergic adverseeffects. In response, the second-generation or so-called “nonsedating”antihistamines, including astemizole, terfenadine, loratadine,cetirizine and fexofenadine, were developed. These compounds havereduced CNS impact and additional antiallergic properties, includinginhibition of mast cell degranulation. Desloratadine, a metabolite ofloratadine, has been categorized as a third-generation antihistamine(McClellan & Jarvis, Drugs 2001; 61: 789-796), and has direct effects oninflammatory mediators such as inhibition of intracellular adhesionmolecule-1 (ICAM-1) expression by nasal epithelium. The importance ofhistamine in sleep regulation is evidenced by the hypnotic effects ofcertain histamine receptor ligands (Mignot et al., Nature NeuroscienceSupplement; 5; 1071-1075), particularly the older generation molecules.

While significant advances have been made in the field of sleepinitiation and prolongation, there continues to be a need in the art forcompounds that are effective as sedative and hypnotic agents, especiallyfor compounds with clinical application to the treatment of insomnia. Inparticular, there remains a need for compounds having improvedselectivity, a quicker onset of action, a shorter half-life and/or theability to penetrate the CNS. The present invention fulfills these needsand other needs, and provides further related advantages.

BRIEF SUMMARY OF THE INVENTION

In brief, this invention is directed to compounds that have utility overa wide range of therapeutic applications, particularly in the context ofinducing sleep, and which compounds have the following general structure(I):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof, wherein R₁, R_(2a), R_(2b), R₃, R₄, R_(5a), R_(5b), L₁, L₂ andn are as defined below.

The compounds of this invention may generally be used to treat a varietyof disorders and/or illnesses, particularly those that benefit frominhibition of one or more histamine receptors. Accordingly, in oneembodiment, methods for treating a condition or disorder are disclosed,the treatment of which can be effected or facilitated by antagonizing ahistamine receptor. In another embodiment, methods are disclosed fortreating sleep disorders, including insomnia, as well as for inducingsleep, sedation and/or hypnosis generally.

The methods of this invention generally involve administering aneffective amount of one or more compounds of this invention, typicallyin the form of a pharmaceutical composition, to an animal (also referredto here as a “patient”, including a human) in need thereof. Accordingly,in still another embodiment, compositions are disclosed containing oneor more compounds of this invention in combination with apharmaceutically acceptable carrier and/or diluent.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To that end, various referencesare set forth herein which describe in more detail certain procedures,compounds and/or compositions, and are hereby incorporated by referencein their entirety.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, this invention is generally directed to compounds thathave utility over a wide range of therapeutic applications, particularlyin the context of sleep induction, and more particularly for treatmentof insomnia.

Accordingly, in one embodiment, this invention is directed to a methodfor treatment of a sleep disorder comprising administering to a patientin need thereof an effective amount of a compound having the followingstructure (I):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof,

wherein:

-   -   R₁ is R_(1a), R_(1b), —OR, —CN, —C(═O)R, —OC(═O)R or —C(═O)OR,        wherein R is alkyl or substituted alkyl;    -   R_(1a) is heterocycle or substituted heterocycle, with the        proviso that R_(1a) is not pyridinyl or substituted pyridinyl;    -   R_(1b) is bicyclic carbocycle or substituted bicyclic        carbocycle;    -   L₁ is a bond or L₂;    -   L₂ is alkanediyl or substituted alkanediyl;    -   R_(2a) and R_(2b) are the same or different and are        independently hydrogen, alkyl or substituted alkyl;    -   R₃ is, at each occurrence, the same or different and        independently alkyl, —OR, —SR, —CN, —CF₃ or halogen, wherein R        is alkyl or substituted alkyl;    -   R₄ is hydrogen or alkyl;    -   R_(5a) and R_(5b) are the same or different and independently        hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)        together with the nitrogen to which they are attached form a        heterocycle or substituted heterocycle; and    -   n is 0, 1 or 2 and represents the number of R₃ groups.

Without intending to be bound by theory, it is believed that thecompounds of this invention function as ligands to one or more histaminereceptors, and are thereby useful in the treatment of a variety ofconditions or diseases associated therewith. In this manner, thecompounds alter or regulate the activity of a histamine receptor,thereby providing a treatment for a condition or disease associated withthat receptor. Thus, compounds of this invention may have utility over abroad range of therapeutic applications, and may be used to treatdisorders or illnesses, including (but not limited to) sleep disorders.Compounds of this invention may be advantageous as sedative hypnotics asthey show one or more enhancements over previously known antihistamines.Some advantages of compounds of the present invention may include anenhanced selectivity profile for H₁ receptor relative to other G-proteincoupled receptors and other proteins in comparison to other knownsedating H₁ ligands. Effects on sleep processes are therefore morespecific. Compounds of the present invention may also show reducedinhibition of cytochrome P₄₅₀ (CYP) enzymes that potentiate druginteractions as well as other proteins associated with the safety ofpharmaceuticals such as the human ether a go-go (hERG) channel. Thesecompounds may also show favorable characteristics relative to otherknown antihistamines, including (but not limited to) improved efficacy,improved quality of sleep, lack of peripheral side effects and optimalpharmacokinetics for use as a sedative. Accordingly, the methods of thisinvention include, in addition to treatment of a sleep disorders asnoted above, treatment of insomnia, as well as for inducing sleep,sedation and/or hypnosis, by administration of an effective amount of acompound of structure (I) as disclosed above to a patient in needthereof.

In another embodiment, compounds are disclosed having the followingstructure (II):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof,

wherein:

-   -   R₁ is R_(1a), R_(1b), —OR, —CN, —C(═O)R, —OC(═O)R or —C(═O)OR,        wherein R is alkyl or substituted alkyl;    -   R_(1a) is heterocycle or substituted heterocycle, with the        proviso that R_(1a) is not pyridinyl or substituted pyridinyl;    -   R_(1b) is bicyclic carbocycle or substituted bicyclic        carbocycle;    -   L₁ is a bond or L₂;    -   L₂ is alkanediyl or substituted alkanediyl;    -   R_(2a) and R_(2b) are the same or different and are        independently hydrogen, alkyl or substituted alkyl, with the        proviso that R_(2a) and R_(2b) are not both hydrogen;    -   R₃ is, at each occurrence, the same or different and        independently alkyl, —OR, —SR, —CN, —CF₃ or halogen, wherein R        is alkyl or substituted alkyl;    -   R₄ is hydrogen or alkyl;    -   R_(5a) and R_(5b) are the same or different and independently        hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)        together with the nitrogen to which they are attached form a        heterocycle or substituted heterocycle; and    -   n is 0, 1 or 2 and represents the number of R₃ groups.

In still another embodiment, compounds are disclosed having thefollowing structure (III):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof,

wherein:

-   -   R₁ is R_(1a), wherein R_(1a) is pyrazinyl, substituted        pyrazinyl, pyridazinyl, substituted pyridazinyl, triazinyl, or        substituted triazinyl;    -   L₁ is a bond or L₂;    -   L₂ is alkanediyl or substituted alkanediyl;    -   R_(2a) and R_(2b) are both hydrogen;    -   R₃ is, at each occurrence, the same or different and        independently alkyl, —OR, —SR, —CN, —CF₃ or halogen, wherein R        is alkyl or substituted alkyl;    -   R₄ is hydrogen or alkyl;    -   R_(5a) and R_(5b) are the same or different and independently        hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)        together with the nitrogen to which they are attached form a        heterocycle or substituted heterocycle; and    -   n is 0, 1 or 2 and represents the number of R₃ groups.

“Alkyl” means a straight chain or branched, noncyclic or cyclic,unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10carbon atoms, while the term “lower alkyl” has the same meaning as alkylbut contains from 1 to 6 carbon atoms. Representative saturated straightchain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, and the like; while saturated branched alkyls includeisopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-cyclohexyl, and the like; while unsaturatedcyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.Cyclic alkyls, also referred to as “homocyclic rings,” and include di-and poly-homocyclic rings such as decalin and adamantyl. Unsaturatedalkyls contain at least one double or triple bond between adjacentcarbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively).Representative straight chain and branched alkenyls include ethylenyl,propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and thelike; while representative straight chain and branched alkynyls includeacetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1 butynyl, and the like.

“Bicyclic carbocycle” means a 7- to 13-membered carbon ring systemcontaining no ring heteroatoms and having two carbon rings which shareat least two carbon atoms, and which may be saturated, partiallyunsaturated or aromatic, such as naphthyl, indanyl,5H-benzocycloheptene, tetrahydronaphthyl, and the like.

“Alkanediyl” means a divalent alkyl from which two hydrogen atoms aretaken from the same carbon atom or from different carbon atoms, such as—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, -cyclopentane-,-cyclohexane-, -cycloheptane-, and the like.

“Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl.

“Arylalkyl” means an alkyl having at least one alkyl hydrogen atomsreplaced with an aryl moiety, such as benzyl (i.e., —CH₂-phenyl),—CH₂-(1- or 2-naphthyl), —(CH₂)₂-phenyl, —(CH₂)₃-phenyl, —CH(phenyl)₂,and the like.

“Heteroaryl” means an aromatic heterocycle ring of 5- to 10-members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and containing at least 1 carbon atom, including both mono- andbicyclic ring systems. Representative heteroaryls include (but are notlimited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl,indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl,oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl,benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atomreplaced with a heteroaryl moiety, such as —CH₂-pyridinyl,—CH₂-pyrimidinyl, and the like.

“Heterocycle” (also referred to herein as a “heterocycle ring”) means a5- to 7-membered monocyclic, or 7- to 14-membered polycyclic,heterocycle ring which is either saturated, unsaturated or aromatic, andwhich contains from 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen heteroatom maybe optionally quaternized, including bicyclic rings in which any of theabove heterocycles are fused to a benzene ring as well as tricyclic (andhigher) heterocyclic rings. The heterocycle may be attached via anyheteroatom or carbon atom. Heterocycles include heteroaryls as definedabove. Thus, in addition to the aromatic heteroaryls listed above,heterocycles also include (but are not limited to) morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Heterocyclealkyl” means an alkyl having at least one alkyl hydrogenatom replaced with a heterocycle, such as —CH₂-morpholinyl, and thelike.

“Halogen” means fluoro, chloro, bromo and iodo.

“Haloalkyl” means an alkyl having at least one hydrogen atom replacedwith halogen, such as trifluoromethyl and the like. Haloalkyl is aspecific embodiment of substituted alkyl, wherein alkyl is substitutedwith one or more halogen atoms.

“Hydroxyalkyl” means an alkyl having at least one hydrogen atomreplaced.

“Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e.,—O-alkyl), such as —O-methyl, —O-ethyl, and the like.

“Thioalkyl” means an alkyl moiety attached through a sulfur bridge(i.e., —S-alkyl) such as —S-methyl, —S-ethyl, and the like.

“Aryloxy” means an aromatic carbocyclic moiety such as phenyl ornaphthyl attached through an oxygen bridge (i.e., —O-aryl) such as—O-phenyl, —O-naphthyl, and the like.

Lastly, the term “substituted” as used herein means any of the abovegroups (i.e., alkyl, alkanediyl, bicyclic carbocycle, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl) wherein atleast one hydrogen atom is replaced with a substituent. In the case ofan oxo substituent (“═O”) two hydrogen atoms are replaced.“Substituents” within the context of this invention include halogen,hydroxy, oxo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl,alkoxy, thioalkyl, haloalkyl, hydroxyalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl, substituted heterocyclealkyl,—NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b)—NR_(a)SO₂R_(b), —OR_(a), —C(═O)R_(a)—C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)NR_(a)R_(b), —SH, —SR_(a), —SOR_(a),—S(═O)₂R_(a), —OS(═O)₂R_(a), —S(═O)₂OR_(a), wherein R_(a) and R_(b) arethe same or different and independently hydrogen, alkyl, haloalkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl or substituted heterocyclealkyl.

In more specific embodiments of structures (I), (II) and (III), L₁ is abond (i.e., a direct bond between R₁ and the carbon atom bearing R_(2a)and R_(2b)), and compounds of this invention have the followingstructure (IV). In an alternative embodiment, L₁ is alkanediyl orsubstituted alkanediyl, such as —CH₂— as represented in structure (V).

As noted above, R_(2a) and R_(2b) are the same or different and areindependently hydrogen, alkyl or substituted alkyl. When R_(2a) andR_(2b) are different, the carbon atom to which R_(2a) and R_(2b) arebonded is a chiral center (i.e., a carbon atom to which four differentgroups are attached). Accordingly, in more specific embodiments ofstructures (I) and (II), R_(2a) and R_(2b) are different, and the carbonto which these groups are bonded is a chiral center, as represented inthe following structure (VI) by the asteric symbol “*” on the chiralcarbon atom. For example, representative R_(2a) and R_(2b) combinationsinclude the following embodiments: R_(2a) is hydrogen and R_(2b) iseither alkyl or substituted alkyl; R_(2a) is alkyl and R_(2b) issubstituted alkyl; R_(2a) is alkyl and R_(2b) is a different alkyl;R_(2a) is substituted alkyl and R_(2b) is a different substituted alkyl.

In a more specific embodiment of structure (VI), R₁ is R_(1a), andR_(1a) is heterocycle or substituted heterocycle.

In more specific embodiment of structures (I) and (III), R_(2a) andR_(2b) are the same, and the carbon to which these groups are bonded isnot a chiral center, as represented in the following structure (VII) bythe symbol “{circumflex over ( )}” on the non-chiral carbon atom. Forexample, representative R_(2a) and R_(2b) combinations include thefollowing embodiments: R_(2a) and R_(2b) are both hydrogen (i.e.,structure (III)); R_(2a) and R_(2b) are both the same alkyl; or R_(2a)and R_(2b) are both the same substituted alkyl.

In a more specific aspect of structure (VII), R₁ is R_(1a), R_(1a) ispyrazinyl or substituted pyrazinyl, and the compounds have the followingstructure (VIII-1) or (VIII-2), respectively:

When L₁ of structure (VIII-1) or (VIII-2) is a bond, the compounds ofthis invention have the following structures (IX-1) or (IX-2),respectively:

In more specific embodiments of structures (I), (II) and (III), L₂ isalkanediyl such as —CH₂— or —CH₂CH₂—, and compounds of this inventionhave the following structures (X-1) or (X-2), respectively:

In another more specific embodiment of structures (I), (II) and (III), nis 0 and R₃ is not present (i.e., n is 0). In another embodiment, n is 1and R₃ is alkyl, —OR, —SR, CN, —CF₃ or halogen, wherein R is alkyl orsubstituted alkyl, or n is 2 and R₃ is, at each occurrence, the same ordifferent and independently alkyl, —OR, —SR, —CN, —CF₃ or halogen,wherein R is alkyl or substituted alkyl.

In another more specific embodiment of structures (I), (II) and (III),R₄ is hydrogen, and in another embodiment R₄ is alkyl including (but notlimited to) lower alkyl such as methyl, ethyl and the like.

In another more specific embodiment of structures (I), (II) and (III),R_(5a) and R_(5b) are the same or different and independently hydrogen,alkyl or substituted alkyl or, alternatively, R_(5a) and R_(5b) togetherwith the nitrogen to which they are attached form a heterocycle orsubstituted heterocycle (such as a heterocyclic ring which is optionallysubstituted with alkyl or substituted alkyl).

In still further and more specific embodiments of structures (I) and(II), L₁ is a bond, R_(2a) is hydrogen, R_(2b) is methyl, and thecompounds of this invention have the following structure (XI):

In more specific embodiments of structure (XI), R₁ is R_(1a), and R_(1a)is pyrazinyl or 5-methyl-1,3,4-oxadiazolyl as represented by thefollowing structures (XII-1) and (XII-2), respectively:

In another more specific embodiment of structure (XI), R₁ is —C(═O)OR,such as —C(═O)O(tert-butyl) as represented in structure (XIII):

In still further and more specific embodiments of structures (I) and(III), R₁ is —OCH₂CH₃, L₁ is a —CH₂—, L₂ is —CH₂CH₂—, R_(2a) ishydrogen, R_(2b) is methyl, and the compounds of this invention have thefollowing structure (XIV):

In more specific embodiment of structures (XI), (XII-1), (XII-2), (XIII)and (XIV), n is 0 and/or R₄ is hydrogen.

Representative compounds of the present invention include the followingand their enantiomers:

(2-Fluoro-ethyl)-methyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

(2-Fluoro-ethyl)-methyl-{2-[6-methyl-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

(2-Fluoro-ethyl)-{2-[6-methoxy-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amine;

Dimethyl-{2-[3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

Dimethyl-{2-[6-methyl-3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

{2-[6-Methoxy-3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

{2-[6-Fluoro-3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

1-{2-[3-(1-Pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-azetidin-3-ol;

2-(1-{2-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyrazine

1-{2-[3-(1-Pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyrazine;

1-(2-{6-Fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-pyrrolidin-3-ol;

1-(2-{6-Fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-azetidin-3-ol;

2-(2-Dimethylamino-ethyl)-1-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-3H-indene-5-carbonitrile;

2-(2-Dimethylamino-ethyl)-1-(1-pyrazin-2-yl-ethyl)-3H-indene-5-carbonitrile;

2-(2-Dimethylamino-ethyl)-1-pyridazin-3-ylmethyl-3H-indene-5-carbonitrile;

2-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-ylmethyl}-pyrazine;

3-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-ylmethyl}-pyridazine;

3-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methyl-3H-inden-1-ylmethyl}-pyridazine;

3-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-fluoro-3H-inden-1-ylmethyl}-pyridazine;

3-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methoxy-3H-inden-1-ylmethyl}-pyridazine;

2-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methyl-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-fluoro-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methoxy-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-fluoro-3H-inden-1-yl}-ethyl)-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methoxy-3H-inden-1-yl}-ethyl)-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-fluoro-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methoxy-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

3-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyridazine;

3-(1-{2-[2-(2,5-Dihydro-pyrrol-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-pyridazine;

2-{1-[2-(2-Azetidin-1-yl-ethyl)-5-fluoro-3H-inden-1-yl]-ethyl}-3-methoxy-pyrazine;

3-{1-[2-(2-Azetidin-1-yl-ethyl)-5-fluoro-3H-inden-1-yl]-ethyl}-pyridazine;

3-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-ylmethyl}-pyridazine;

3-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methyl-3H-inden-1-ylmethyl}-pyridazine;

3-{5-Fluoro-2-[2-(3-fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-ylmethyl}-pyridazine;

3-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methoxy-3H-inden-1-ylmethyl}-pyridazine;

1-[2-(3-Pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-pyrrolidin-3-ol;

1-{2-[6-Methyl-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-pyrazine;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methoxy-3H-inden-1-yl}-ethyl)-pyrazine;

1-{2-[6-Methoxy-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

1-{2-[6-Fluoro-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

1-{2-[3-(1-Pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

1-{2-[6-Methoxy-3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

1-{2-[6-Fluoro-3-(1-pyridazin-3-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

3-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyridazine;

3-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-pyridazine;

3-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methoxy-3H-inden-1-yl}-ethyl)-pyridazine;

3-(1-{5-Fluoro-2-[2-(3-fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-pyridazine;

1-(2-{3-[1-(3-Methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-pyrrolidin-3-ol;

1-(2-{3-[1-(3-Methoxy-pyrazin-2-yl)-ethyl]-6-methyl-1H-inden-2-yl}-ethyl)-pyrrolidin-3-ol;

1-(2-{6-Methoxy-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-pyrrolidin-3-ol;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methyl-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methoxy-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-(1-{5-Fluoro-2-[2-(3-fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-3-methoxy-pyrazine;

2-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methyl-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-5-methoxy-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

2-{5-Fluoro-2-[2-(3-fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-ylmethyl}-3-methoxy-pyrazine;

3-{1-[2-(2-Dimethylamino-ethyl)-5-methoxy-3H-inden-1-yl]-ethyl}-pyrazin-2-ol;

2-({2-[3-(2-Methoxy-1-methyl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amino)-ethanol;

Dimethyl-{2-[3-(1-pyrazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

Dimethyl-{2-[6-methyl-3-(1-pyrazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

{2-[6-Methoxy-3-(1-pyrazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

{2-[6-Fluoro-3-(1-pyrazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

Dimethyl-{2-[3-(1-[1,2,3]triazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

Dimethyl-{2-[6-methyl-3-(1-[1,2,3]triazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

{2-[6-Fluoro-3-(1-[1,2,3]triazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

{2-[6-Methoxy-3-(1-[1,2,3]triazol-1-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;

2-({2-[6-Methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amino)-ethanol;

1-{2-[6-Methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

1-{2-[6-Methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-azetidin-3-ol;

(2-Fluoro-ethyl)-{2-[6-methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amine;

2-(Methyl-{2-[3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amino)-ethanol;

(2-Fluoro-ethyl)-methyl-{2-[3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;

1-{2-[3-(1-Thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-pyrrolidin-3-ol;

2-(1-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-thiazole;

1-{2-[3-(1-Thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-azetidin-3-ol;

2-(1-{2-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-3H-inden-1-yl}-ethyl)-thiazole;

2-(Methyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amino)-ethanol;

2-({2-[6-Fluoro-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amino)-ethanol;

(2-Fluoro-ethyl)-{2-[6-fluoro-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-methyl-amine;

(2-Fluoro-ethyl)-(2-{6-fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-methyl-amine;

2-[(2-{6-Fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-methyl-amino]-ethanol;

2-[(2-{3-[1-(3-Methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-methyl-amino]-ethanol;

(2-Fluoro-ethyl)-(2-{3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-methyl-amine;and

2-{2-[2-(3-Fluoro-pyrrolidin-1-yl)-ethyl]-3H-inden-1-ylmethyl}-pyrazine.

The compounds of the present invention may generally be utilized as thefree acid or free base. Alternatively, the compounds of this inventionmay be used in the form of acid or base addition salts. Acid additionsalts of the free amino compounds of the present invention may beprepared by methods well known in the art, and may be formed fromorganic and inorganic acids. Suitable organic acids include maleic,fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic,trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric,gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic,glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acidsinclude hydrochloric, hydrobromic, sulfuric, phosphoric, and nitricacids. Base addition salts included those salts that form with thecarboxylate anion and include salts formed with organic and inorganiccations such as those chosen from the alkali and alkaline earth metals(for example, lithium, sodium, potassium, magnesium, barium andcalcium), as well as the ammonium ion and substituted derivativesthereof (for example, dibenzylammonium, benzylammonium,2-hydroxyethylammonium, and the like). Thus, the term “pharmaceuticallyacceptable salt” of structures (I), (II) and (III) is intended toencompass any and all acceptable salt forms.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structures (I), (II) and (III) in vivo when such prodrug isadministered to a patient. Prodrugs are generally prepared by modifyingfunctional groups in a way such that the modification is cleaved, eitherby routine manipulation or in vivo, yielding the parent compound.Prodrugs include, for example, compounds of this invention whereinhydroxy, amine or sulfhydryl groups are bonded to any group that, whenadministered to a patient, cleaves to form the hydroxy, amine orsulfhydryl groups. Thus, representative examples of prodrugs include(but are not limited to) acetate, formate and benzoate derivatives ofalcohol and amine functional groups of the compounds of structures (I),(II) and (III). Further, in the case of a carboxylic acid (—COOH),esters may be employed, such as methyl esters, ethyl esters, and thelike.

With regard to stereoisomers, the compounds of structures (I), (II) and(III) may have chiral centers and may occur as racemates, racemicmixtures and as individual enantiomers or diastereomers. All suchisomeric forms are included within the present invention, includingmixtures thereof. Compounds of structures (I), (II) and (III) may alsopossess axial chirality which may result in atropisomers. Furthermore,some of the crystalline forms of the compounds of structures (I), (II)and (III) may exist as polymorphs, which are included in the presentinvention. In addition, some of the compounds of structures (I), (II)and (III) may also form solvates with water or other organic solvents.Such solvates are similarly included within the scope of this invention.

The compounds of this invention may be prepared by known organicsynthesis techniques, including the methods of the following ReactionSchemes 1-8, as well as by the more detailed methods disclosed in theExamples.

Indene a reacts with 2-bromo-propionic acid methyl ester to form theindene propionic acid methyl ester b. Indene a reacts with2-bromo-propionic acid t-butyl ester in the presence of n-butyllithiumand base to form the protected indene propionic acid ester c. Reactionof compound c with TFA gives rise to the cleavage of the t-butyl groupto afford the free acid d. Compound d reacts with HOBt, DIEA, EDCl andNH₃:H₂O in THF to yield the amide e. Reagent e reacts withtrifluoroacetic acid anhydride in the presence of pyridine in THF toafford nitrile f which further reacts with trimethylsilylazide to affordtetrazole g.

Heterocyclic ring adds to indene propionic acid d (Reaction Scheme 1)via the reactions illustrated above (Reaction Scheme 2.) Reagent dreacts with (COCl)₂ and the amino ethanol in CH₂Cl₂ followed byconversion to the mesylate and treatment with NaOH to yield oxazoline h.Reaction of d with (COCl)₂ and the amino ketone or the amino alcoholfollowed by oxidation affords the oxazole i. Reaction of d with POCl₃and the acid hydrazide yields the oxadiazole j. Reaction of d with(COCl)₂ and the amino thiol in CH₂Cl₂ affords thiazoline k. Reaction ofd with (COCl)₂ and the amino ketone followed by reflux with Lawesson'sreagent in toluene affords thiazole 1. Reaction of d with (COCl)₂ andthe acid hydrazide followed by reflux with Lawesson's reagent in tolueneaffords thiadiazole m.

To a solution of LDA is added with stirring ethyl heterocycle reagent n.A solution of indanone o is added with stirring. At the completion ofthe reaction, water is added to quench. The mixture is extracted withEt₂O, washed with aqueous NaHCO₃ solution, and extracted with HClaqueous solution. The combined HCl layers are heated. After cooling toroom temperature, the mixture is neutralized with cooled NH₄OH andextracted with EtOAc. The organic layer is dried over Na₂SO₄ andconcentrated to afford compound p.

Reagent b (Reaction Scheme 1) reacts with a mixture of the oxime andn-butyllithium in THF at low temperature and then with H₂SO₄ in THF toyield the isoxazole q.

Indene a (Reaction Scheme 1) reacts with acetaldehyde, n-butyllithium,and BF₃ in ET₂O to form alcohol reagent r. Reagent r reacts withmethanesulfonyl chloride and DIEA in dichloromethane to afford protectedreagent s. Addition of heterocyclic reagent “HetN,” wherein saidheterocyclic reagent contains a nitrogen with a dissociable proton inthe ring, to reagent s affords compound t. Reaction of azide withreagent s affords reagent u. Addition of substituted acetylene toreagent u affords the substituted triazole compounds v′ and v″. Reactionof reagent u with (trimethylsilyl)acetylene affords reagent w whichundergoes trimethysilyl loss resulting from reaction withtetrabutylammonium fluoride to afford triazole compound x.

Alkylation of an appropriate 1-indanone with hal-L₂-N(R_(5a)R_(5b)) inthe presence of a strong base such as lithium diisopropylamide in asolvent such as THF gives the 2-substituted indanone.

An appropriately substituted indene may be alkylated with a compoundsuch as halogen—C(R_(2a)R_(2b))-L₁-R₁ in the presence of an alkyllithiumcatalyst in a solvent such as THF.

Alkylation of an appropriate 1-indanone with H-L₂-NR_(5a)R_(5b) in thepresence of a strong base such as lithium diisopropylamide in a solventsuch as THF gives a substituted indene.

For the purposes of administration, the compounds of the presentinvention may be formulated as pharmaceutical compositions.Pharmaceutical compositions of the present invention comprise a compoundof structures (I), (II) or (III) and a pharmaceutically acceptablecarrier and/or diluent. The compound is present in the composition in anamount that is effective to treat a particular disorder of interest, andpreferably with acceptable toxicity to the patient. Typically, thepharmaceutical composition may include a compound of this invention inan amount ranging from 0.1 mg to 250 mg per dosage depending upon theroute of administration, and more typically from 1 mg to 60 mg.Appropriate concentrations and dosages can be readily determined by oneskilled in the art.

Pharmaceutically acceptable carrier and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets that contain, inaddition to a compound of this invention, dispersing and surface activeagents, binders, and lubricants. One skilled in this art may furtherformulate the compound in an appropriate manner, and in accordance withaccepted practices, such as those disclosed in Remington'sPharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa.1990.

The compounds of this invention may be evaluated for their ability tobind to histamine receptor ligands, which may be determined bytechniques known in this field. For example, Example 26 provides ageneral procedure for calculating the binding to the histamine H₁receptor by a standard binding assay, while Example 27 provides ageneral procedure for determining the sedative effects of test compoundsemploying electroencephalography and electromyography.

In other embodiments, the present invention provides a method fortreating a condition related to a histamine receptor. Such methodsinclude administration of a compound of structure (I), (II) or (III) toa warm-blooded animal (including a human) in an amount sufficient totreat the condition. In this context, “treat” includes prophylacticadministration. Such methods include systemic administration of compoundof this invention, typically in the form of a pharmaceutical compositionas discussed above. As used herein, systemic administration includesoral and parenteral methods of administration. For oral administration,suitable pharmaceutical compositions include powders, granules, pills,tablets, and capsules as well as liquids, syrups, suspensions, andemulsions. These compositions may also include flavorants,preservatives, suspending, thickening and emulsifying agents, and otherpharmaceutically acceptable additives. For parental administration, thecompounds of the present invention can be prepared in aqueous injectionsolutions that may contain buffers, antioxidants, bacteriostats, andother additives commonly employed in such solutions.

The following examples are provided for purposes of illustration and notlimitation.

EXAMPLES

Analytical HPLC-MS Method 1

Platform: Agilent 1100 series: equipped with an auto-sampler, an UVdetector (220 nM and 254 nM), a MS detector (APCI);

HPLC column: YMC ODS AQ, S-5, 5μ, 2.0×50 mm cartridge;

HPLC gradient: 1.0 mL/minute, from 10% acetonitrile in water to 90%acetonitrile in water in 2.5 minutes, maintaining 90% for 1 minute. Bothacetonitrile and water have 0.025% TFA.

Analytical HPLC-MS Method 2

Platform: Agilent 1100 series: equipped with an auto-sampler, an UVdetector (220 nM and 254 nM), a MS detector (APCI);

HPLC column: Phenomenex Synergi-Max RP, 2.0×50 mm column;

HPLC gradient: 1.0 mL/minute, from 5% acetonitrile in water to 95%acetonitrile in water in 13.5 minutes, maintaining 95% for 2 minute.Both acetonitrile and water have 0.025% TFA.

Analytical HPLC-MS Method 3

Platform: Agilent 1100 series: equipped with an auto-sampler, an UVdetector (220 nM and 254 nM), a MS detector (electrospray);

HPLC column: XTerra MS, C₁₈, 5μ, 3.0×250 mm column;

HPLC gradient: 1.0 mL/minute, from 10% acetonitrile in water to 90%acetonitrile in water in 46 minutes, jump to 99% acetonitrile andmaintain 99% acetonitrile for 8.04 minutes. Both acetonitrile and waterhave 0.025% TFA.

Analytical HPLC-MS Method 4

Platform: Agilent 1100 series: equipped with an auto-sampler, an UVdetector (220 nM and 254 nM), a MS detector (APCI) and Berger FCM 1200CO₂ pump module;

HPLC column: Berger Pyridine, PYR 60A, 6μ, 4.6×150 mm column;

HPLC gradient: 4.0 mL/minute, 120 bar; from 10% methanol insupercritical CO₂ to 60% methanol in supercritical CO₂ in 1.67 minutes,maintaining 60% for 1 minute. Methanol has 1.5% water. Backpressureregulated at 140 bar.

Preparative HPLC-MS

Platform: Shimadzu HPLC equipped with a Gilson 215 auto-sampler/fractioncollector, UV detector and a PE Sciex API150EX mass detector;

HPLC column: BHK ODS-O/B, 5μ, 30×75 mm

HPLC gradient: 35 mL/minute, 10% acetonitrile in water to 100%acetonitrile in 7 minutes, maintaining 100% acetonitrile for 3 minutes,with 0.025% TFA.t_(R)=retention time (in minutes)Chiral HPLC

Platform: Dionex P680A and P680P pumps, Dionex PAD 100 photodiode arraydetector, Jasco CD 2095 plus chiral detector, Gilson 215 liquid handlerp HPLC Columns: Chiral Technologies, Chiralpak AD-H (chiral profiles1-8), Chiralcel OD-H (chiral profile 9). Analytical Columns are 0.46×25cm, 5 μm; preparative columns are 2×25 cm, 5 μm.

Isocratic elutant: Flow Rate: 0.3 to 1.0 mL/min for analytical and 8 to15 mL/min for preparative.

Elutant profile 1: Hexane/isopropyl alcohol 99/1 with 0.1%isopropylamine

Elutant profile 2: Hexane/isopropyl alcohol 97/3 with 0.1%isopropylamine

Elutant profile 3: Hexane/ethyl alcohol 97/3 with 0.1% diethylamine

Elutant profile 4: Hexane/isopropyl alcohol 95/5 with 0.1% diethylamine

Elutant profile 5: Hexane/isopropyl alcohol 85/15 with 0.1% diethylamine

Elutant profile 6: Hexane/ethyl alcohol 95/5 with 0.1% diethylamine

Elutant profile 7: Hexane/ethyl alcohol 9/1 with 0.1% diethylamine

Elutant profile 8: Hexane/isopropyl alcohol 9/1 with 0.1% diethylamine

Elutant profile 9: Methanol with 0.1% diethylamine.

Abbreviations

LDA: Lithium diisopropylamide

THF: Tetrahydrofuran

HPLC: High performance liquid chromatography

TFA: Trifluoroacetic acid

CHO: Chinese hamster ovary

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBT: 1-Hydroxybenzotriazole

DIEA: Diisopropylethylamine

MsCl: Methanesulfonyl Chloride

Example 1 SYNTHESIS OF REAGENTN,N-DIMETHYL-2-(1-OXO-INDAN-2-YL)-ACETAMIDE

To a solution of 1-indanone (26.4 g, 200 mmol) in THF (400 mL) at −78°C., LDA (100 mL, 2 M in THF/toluene, 200 mmol) was added. After stirringat −78° C. for an hour, 2-chloro-N,N-dimethylacetamide (24.4 g, 200mmol) was added. The resultant mixture was stirred at −78° C. for 3hours and then warmed to room temperature overnight. NH₄Cl (saturated,200 mL) was added to quench the reaction. The mixture was extracted withEtOAc (2×250 mL). The combined organic solution was washed with water(200 mL), dried over Na₂SO₄, concentrated and purified by flashchromatography (hexane:EtOAc, 3:2) to give N,N-dimethyl-2-(1-oxo-indan-2-yl)-acetamide 1a as a pale yellow oil,41%yield. (MH⁺=218.3)

The following compounds were also made according to this procedure:

-   -   2-(5-Chloro-1-oxo-indan-2-yl)-N,N-dimethyl-acetamide 1b, 38%        yield. (MH⁺=251.9)    -   N,N-Dimethyl-2-(5-methyl-1-oxo-indan-2-yl)-acetamide 1c, 22%        yield. (MH⁺=231.9)    -   2-(5-Methoxy-1-oxo-indan-2-yl)-N,N-dimethyl-acetamide 1d, 60%        yield. (MH⁺=247.9)    -   2-(5-Fluoro-1-oxo-indan-2-yl)-N,N-dimethyl-acetamide 1e, 42%        yield. (MH⁺=235.9)

Example 2 SYNTHESIS OF REAGENT 2-(2-DIMETHYLAMINO-ETHYL)-INDAN-1-ONE

To a solution of LiAlH₄ (7.8 g, 200 mmol) in THF (300 mL) at 0° C.,N,N-dimethyl-2-(1-oxo-indan-2-yl)-acetamide 1a (10 g, 46 mmol) in THF(40 mL) was added slowly. The reaction was allowed to stir at roomtemperature for half an hour and then at reflux for 6 hours. Thereaction was cooled to room temperature and carefully quenched by thesequential addition of H₂O (7.6 mL), 15% NaOH (7.6 mL) and H₂O (22.8mL). The mixture was stirred for a half hour, and the solid was filteredoff using a celite pad and washed with excess THF. The combinedfiltrates were dried over Na₂SO₄ and concentrated to provide2-(2-dimethylamino-ethyl)-indan-1-ol 2a as a yellow oil. A mixture of2-(2-dimethylamino-ethyl)-indan-1-ol 2a, ^(t)BuOK (11.2 g, 100 mmol) andbenzophenone (36.4 g,200 mmol) in anhydrous benzene (200 mL) wasrefluxed for 18 hours under N₂. The cooled mixture was poured into iceand extracted with 10% HCl until the HCl solution was colorless. Thecombined acid extracts were washed with Et₂O (300 mL) and added dropwisewith stirring into NH₄OH and ice. This basic solution was extractedthrice with Et₂O (300 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated and purified by flashchromatography (CHCl₃:MeOH:NH₄OH, 95:5:0.2) to give2-(2-dimethylamino-ethyl)-indan-1-one 2b as a pale yellow oil in 79%yield. (MH⁺=204.2).

The following compounds were also made according to this procedure:

-   -   2-(2-Dimethylamino-ethyl)-5-fluoro-indan-1-one 2c, 42% yield.        (MH⁺=221.9)    -   2-(2-Dimethylamino-ethyl)-5-chloro-indan-1-one 2d, 81% yield.        (MH⁺=237.9)    -   2-(2-Dimethylamino-ethyl)-5-methyl-indan-1-one 2e, 62% yield.        (MH⁺=217.9)    -   2-(2-Dimethylamino-ethyl)-5-methoxy-indan-1-one 2f, 54% yield.        (MH⁺=233.9)

Example 3 SYNTHESIS OF REAGENT [2-(1H-INDEN-2-YL)-ENTHYL]-DIMETHYL-AMINE

To a solution of LiAlH₄ (7.8 g, 200 mmol) in THF (300 mL) at 0° C.,N,N-dimethyl-2-(1-oxo-indan-2-yl)-acetamide 1a (10 g, 46 mmol) in THF(40 mL) was added slowly. The reaction was allowed to stir at roomtemperature for half an hour and then at reflux for 6 hours. Thereaction was cooled to room temperature and carefully quenched by thesequential addition of H₂O (7.6 mL), 15% NaOH (7.6 mL) and H₂O (22.8mL). The mixture was stirred for a half hour, and the solid was filteredoff using a celite pad and washed with excess THF. The combinedfiltrates were dried over Na₂SO₄ and concentrated to provide2-(2-dimethylamino-ethyl)-indan-1-ol 2a as a yellow oil.2-(2-Dimethylamino-ethyl)-indan-1-ol 2a was dissolved in acetic acid(120 mL) and concentrated HCl (40 mL), and the resultant mixture wasrefluxed for 2 hours. Most of the solvent was evaporated in vacuo. Theresidue was diluted with water (200. mL) and washed with ether (50 mL).The aqueous solution was basified with NH₄OH, extracted twice with ether(250 mL), dried over Na₂SO₄, concentrated and purified by flashchromatography (CHCl₃:MeOH:NH₄OH, 98:2:0.2) to give a pale yellow oil,[2-(1H-inden-2-yl)-ethyl]-dimethyl-amine 3a, in 83% yield. (MH⁺=188.0)

In a similar manner [2-(6-methoxy-1H-inden-2-yl)-ethyl]-dimethyl-amine3b was prepared in 15% yield. MH⁺=217.9

Example 4DIMETHYL-{2-[3-(1-PYRAZIN-2-YL-ETHYL)-1H-INDEN-2-YL]-ETHYL}-AMINE

To a solution of LDA (1 mL, 2 N solution in THF, 2 mmol) in Et₂O (5 mL)at 0° C., 2-ethylpyrazine (238 mg, 2.2 mmol) in Et₂O (1 mL) was addedslowly, and the reaction mixture was stirred at 0° C. for 30 minutes. Asolution of 2-(2-dimethylamino-ethyl)-indan-1-one 2b (203 mg, 1 mmol) inEt₂O (1 mL) was added. The resultant mixture was stirred at 0° C. fortwo hours. A small piece of chip ice was added to quench the reaction.The mixture was extracted with Et₂O, washed with NaHCO₃ aqueoussolution, then extracted with 20% HCl (2×5 mL). The combined HCl layerswere heated to 100° C. for 1 hour. After cooling to room temperature,the mixture was neutralized with cooled NH₄OH and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and concentrated to givedimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}amine 4-1 asa red oil which was purified by HPLC yielding the TFA salt. Chiral HPLCseparation on 4-1 using a Chiraltech Chiralpak AD-H column andhexane:isopropyl alcohol 99:1 (with 0.1% isopropylamine) as elutantyielded enantiomers 4-5 and 4-6.

The following compounds were made according to this procedure:

No. R₁ R_(2b) R₃ MW MH⁺ t_(R) (method) 4-1 Pyrazin-2-yl CH₃ H 293.41294.2 3.700 (2) 4-2 Pyrimidin-4-yl CH₃ H 293.41 294.0 3.997 (2) 4-3Pyrazin-2-yl H H 279.38 280.0 3.441 (2) 4-4 3-methoxy-pyrazin-2-yl CH₃ H323.44 324.1 4.602 (2) 4-5 Pyrazin-2-yl (S)-CH₃ H 293.41 294.1 4.091 (2)profile 1 4-6 Pyrazin-2-yl (R)-CH₃ H 293.41 294.1 4.057 (2) profile 14-7 3-methoxy-pyrazin-2-yl (R-)CH₃ H 323.44 323.9 4.443 (2) profile 24-8 3-methoxy-pyrazin-2-yl (S)-CH₃ H 323.44 323.9 4.425 (2) profile 24-9 3-methyl-pyrazin-2-yl H H 293.41 294.0 3.530 (2) 4-10 pyridazin-3-ylH H 279.38 280.0 3.023 (2) 4-11 3-methoxy-pyrazin-2-yl H H 309.41 310.04.279 (2) 4-12 pyrazin-2-yl CH₃, CH₃ H 307.44 308.1 3.883 (2) 4-135-methyl-pyrazin-2-yl H H 293.41 294.0 3.823 (2) 4-146-methyl-pyrazin-2-yl H H 293.41 294.0 3.801 (2) 4-15 pyrimidin-2-yl H H279.38 280.0 3.323 (2) 4-16 3-ethoxy-pyrazin-2-yl H H 323.44 323.9 4.861(2) 4-17 6-propoxy-pyrazin-2-yl H H 337.46 337.9 5.300 (2) 4-18pyrazin-2-yl H Cl 313.83 314.0 4.223 (2) 4-19 3-methoxy-pyrazin-2-yl HCl 343.86 344.1 18.71 (3) 4-20 3-methoxy-pyrazin-2-yl CH₃ Cl 357.88358.1 19.66 (3) 4-21 pyridazin-3-yl H Cl 313.83 313.8 4.027 (2) 4-223-methoxy-pyrazin-2-yl (S)-CH₃ Cl 357.88 357.8 5.195 (2) profile 3 4-233-methoxy-pyrazin-2-yl (R)-CH₃ Cl 357.88 357.8 5.177 (2) profile 3 4-24pyrazin-2-yl H CH₃ 293.41 293.9 4.008 (2) 4-25 pyridazin-3-yl H CH₃293.41 294.1 3.862 (2) 4-26 pyrazin-2-yl CH₃ CH₃ 307.44 307.9 4.366 (2)4-27 3-methoxy-pyrazin-2-yl CH₃ CH₃ 337.46 337.9 5.113 (2) 4-28pyrazin-2-yl (R)-CH₃ CH₃ 307.44 307.9 4.337 (2) profile 4 4-29pyrazin-2-yl (S)-CH₃ CH₃ 307.44 307.9 4.336 (2) profile 4 4-303-methoxy-pyrazin-2-yl (R)-CH₃ CH₃ 337.46 337.9 5.087 (2) profile 5 4-313-methoxy-pyrazin-2-yl (S)-CH₃ CH₃ 337.46 337.9 5.100 (2) profile 5 4-32pyrazin-2-yl H F 297.38 297.9 3.706 (2) 4-33 pyridazin-3-yl H F 297.38297.9 3.308 (2) 4-34 3-methoxy-pyrazin-2-yl H F 327.40 327.9 4.558 (2)4-35 3-methoxy-pyrazin-2-yl Me F 341.43 341.9 4.833 (2) 4-363-methoxy-pyrazin-2-yl (R)-CH₃ F 341.43 341.9 4.919 (2) profile 6 4-373-methoxy-pyrazin-2-yl (S)-CH₃ F 341.43 341.8 4.878 (2) profile 6 4-383-ethoxy-pyrazin-2-yl Me F 355.45 356.1 5.212 (2) 4-393-methoxy-pyrazin-2-yl Et F 355.45 356.1 5.294 (2) 4-40 pyrazin-2-yl HOCH₃ 309.41 310.1 3.415 (2) 4-41 pyrazin-2-yl Me OCH₃ 323.44 323.9 3.947(2) 4-42 pyridazin-3-yl H OCH₃ 309.41 309.9 3.253 (2) 4-433-methoxy-pyrazin-2-yl Me OCH₃ 353.46 353.9 4.565 (2) 4-443-methoxy-pyrazin-2-yl (S)-CH₃ OCH₃ 353.46 354.1 4.563 (2) profile 74-45 3-methoxy-pyrazin-2-yl (R)-CH₃ OCH₃ 353.46 354.1 4.533 (2) profile7 4-46 pyrazin-2-yl (R)-CH₃ OCH₃ 323.44 323.9 3.710 (2) profile 7 4-47pyrazin-2-yl (S)-CH₃ OCH₃ 323.44 323.9 3.774 (2) profile 7 4-483-hydroxy-pyrazin-2-yl CH₃ H 309.4 310.1 3.657 (2) 4-493-hydroxy-pyrazin-2-yl (R)-CH₃ F 327.4 328.0 3.941 (2) 4-503-ethoxy-pyrazin-2-yl (R)-CH₃ F 355.45 356.1 5.261 (2) profile 4 4-513-ethoxy-pyrazin-2-yl (S)-CH₃ F 355.45 356.1 5.286 (2) profile 4

Example 5DIMETHYL-{2-[3-(1-THIAZOL-2-YL-ETHYL)-1H-INDEN-2-YL]-ETHYL}-AMINE

To a solution of 2-ethylthiazole (250 mg, 2.2 mmol) in Et₂O (4 mL) at−78° C., n-BuLi (1.3 mL, 1.6 N solution in n-hexane, 2 mmol) was added,and the reaction mixture was stirred at −78° C. for 2 hours. A solutionof 2-(2-dimethylamino-ethyl)-indan-1-one 2b (203 mg, 1 mmol) in Et₂O (1mL) was added. The resultant mixture was stirred at −78° C. for 5 hours.A small piece of ice chip was added to quench the reaction at −78° C.The mixture was extracted with Et₂O, washed with NaHCO₃ aqueoussolution, then extracted with 20% HCl (2×5 mL). The combined HCl layerswere heated to 100° C. for 1 hour. After cooling to room temperature,the mixture was neutralized with cooled NH₄OH and extracted with EtOAc.The organic layers were dried over Na₂SO₄ and concentrated to give a redoil, which was purified by HPLC to givedimethyl-{2-[3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine 5-1 asa TFA salt (157 mg, 38% yield). (MH⁺=299.1). Chiral HPLC gaveenantiomers 5-2 and 5-3.

2-Ethyl-5-trimethylsilanyl-thiazole may be used in place of2-ethylthiazole as shown in the alternative procedure below. To asolution of 2-ethylthiazole (2.26 g, 20 mmol) in THF (50 mL) at −50° C.under N₂, nBuLi (12.5 mL, 1 M solution in hexanes, 20 mmol) was added.The solution was stirred at −50° C. for 30 min and chlorotrimethylsilane(2.61 g, 24 mmol, 1.2 eq.) was added dropwise. After removal of thecooling bath, the mixture was allowed to slowly reach room temperatureovernight. The reaction was quenched with sat. NaHCO₃ and extracted withEtOAc, dried over Na₂SO₄, concentrated and distilled (45-48° C./10 mmHg)to give 1.3 g of 2-ethyl-5-trimethylsilanyl-thiazole (33% yield).

To a cooled solution (−78° C.) of 2-ethyl-5-trimethylsilanyl-thiazole(0.243 g, 1.32 mmol) in THF (2 mL), n-BuLi (0.82 mL, 1.6 M) was slowlyadded. The solution was stirred for 30 min at −78° C. A solution of2-(2-dimethylamino-ethyl)-5-methyl-indan-1-one 2e (0.143 g, 0.66 mmol)in THF (2 mL) was added slowly and stirring was continued for 16 hrswhile the temperature slowly increased to room temperature. The solventwas removed in vacuo and dichloromethane was added. The organic layerwas washed with water, dried (MgSO₄), filtered and concentrated invacuo. The residue was treated with 20% HCl (3 mL) for 5 hours at roomtemperature. Neutralization with NH₄OH was followed by extraction withdichloromethane. The separated organic layer was washed with water andconcentrated in vacuo. Purification by preparative HPLC affordeddimethyl-(2-{6-methyl-3-[1-(5-trimethylsilanyl-thiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amineas a TFA salt. MW=370.6, MH⁺=371,; t_(R)=5.398 (method 2). The salt wasneutralized by ammonia and extracted with dichloromethane. The organiclayer was dried over MgSO₄, filtered and concentrated to give 0.12 g offree base (47% yield) which was dissolved in acetonitrile and a 48-51%aqueous solution of HF (0.12 g, 3.1 mmol) was added. The reactionmixture was stirred overnight at room temperature, neutralized withammonia and extracted with dichloromethane. The combined organic layerswere dried (MgSO₄), filtered and concentrated in vacuo to give 5-1. Theenantiomers were separated using chiral HPLC.

The following compounds were made according to this procedure:

No. R₃ R_(2b) MW MH⁺ t_(R) (method 2) 5-1 —H CH₃ 298.45 299 4.238 5-2 —H(R)-CH₃ 298.45 299 4.292 profile 6 5-3 —H (S)-CH₃ 298.45 299 4.299profile 6 5-4 —CH₃ (R)-CH₃ 312.48 313 4.654 profile 7 5-5 —CH₃ (S)-CH₃312.48 313 4.619 profile 7 5-6 —OCH₃ —CH₃ 328.48 328.8 4.234 5-7 —OCH₃(R)-CH₃ 328.48 329 4.310 profile 6 5-8 —OCH₃ (S)-CH₃ 328.48 329 4.325profile 6 5-9 —F CH₃ 316.44 317 4.503 5-10 —F (R)-CH₃ 316.44 317 4.524profile 7 5-11 —F (S)-CH₃ 316.44 317 4.495 profile 7

Example 6{2-[3-(2-ETHOXY-1-METHYL-ETHYL)-1H-INDEN-2-YL]-ETHYL}-DIMETHYL-AMINE

To a solution of [2-(1H-inden-2-yl)-ethyl]-dimethyl-amine 3a (28 mg,0.15 mmol) in THF (1.5 mL) at −78° C., n-butyllithium (0.1 mL, 1.6 Msolution in n-hexane, 0.16 mmol) was added. After stirring at −78° C.for 1 hour, 2-iodopropyl ethyl ether (42 mg, 0.2 mmol) was added. Theresultant mixture warmed to room temperature overnight. Water (5 mL) andEt₂O (5 mL) were added. The organic layer was isolated, dried overNa₂SO₄ and concentrated to give an oil, which was purified by HPLC togive{2-[3-(2-ethoxy-1-methyl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine 6-1as the TFA salt, 6% yield. (MH⁺=274.3)

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 6-1 —CH₂OCH₂CH₃ 273.42 274.3 5.012 6-2—CH₂OCH₃ 259.39 260.1 4.225

Example 7 2-[2-(2-DIMETHYLAMINO- ETHYL)-3H-INDEN-1-YL]-PROPIONIC ACIDTERT- BUTYL ESTER

To a solution of [2-(1H-inden-2-yl)-ethyl]-dimethyl-amine 3a (28 mg,0.15 mmol) in THF (1.5 mL) at −78° C., n-butyllithium (100 μL, 0.16mmol,1.6M in hexanes) was added. After stirring at −78° C. for 1 hour,2-bromo-propionic acid tert-butyl ester (0.2 mmol) was added. Theresultant mixture was warmed to room temperature overnight. SaturatedNaHCO₃ (5 mL) and Et₂O (5 mL) were added. The organic layer was isolatedand dried over Na₂SO₄ and concentrated to give an oil, which waspurified by HPLC to give2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-propionic acid tert-butylester as the TFA salt: compound 7-1. (MH⁺=316.2). To a solution ofcompound 7-1 (9.42 mmol) in dichloromethane (10 mL) at 0° C., TFA (5 mL)was added. After stirring at room temperature overnight, the resultantmixture was concentrated in vacuo. Ethyl acetate was added to theresidue with sonication.2-[2-(2-Dimethylamino-ethyl)-3H-inden-1-yl]-propionic acid 7-2 wasobtained as a white precipitate TFA salt: 65% yield. (MH⁺=260.0)

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 7-1 —C(O)OC(CH₃)₃ 315.45 316.2 5.347 (2)7-2 —C(O)OH 259.35 260.0 3.369 (2) 7-3 —C(O)OCH₃ 273.37 274.0 1.680 (1)

Example 8DIMETHYL-(2-{3-[1-(5-METHYL-[1,3,4]OXADIAZOL-2-YL)-ETHYL]-1H-INDEN-2-YL}-ETHYL)-AMINE

To a solution of compound 7-2 (50 mg, 0.193 mmol) in POCl₃ (5.36 mmol,0.5 mL) was added N-acetyl hydrazide (16 mg, 0.21 mmol.) The reactionmixture was refluxed under nitrogen atmosphere for 2h, cooled, pouredover ice and rendered basic to pH 7-8 using concentrated NH₄OH. To theice-cold aqueous layer was added 2 mL of brine, and the mixture wasextracted with methylene chloride (3×1 mL). The organic layers werecombined, dried over MgSO₄, and filtered, and the solvent was removed invacuo to give a dark oil which was purified by flash columnchromatography (NH₄OH:MeOH:CH₂Cl₂, 1:5:94) to givedimethyl-(2-{3-[1-(5-methyl-[1,3,4]oxadiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine8-1, 31% yield. (MH⁺=298.2)

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 8-1 5-methyl-[1,3,4]oxadiazol-2-yl 297.40298.2 3.500 8-2 5-phenyl-[1,3,4]oxadiazol-2-yl 359.47 360.2 4.920

Example 9DIMETHYL-(2-{3-[1-(5-PHENYL-OXAZOL-2-YL)-ETHYL]-1H-INDEN-2-yl}-ETHYL)-AMINE

To a solution of 7-2 (99 mg, 0.38 mmol) in THF (1 mL) was added HOBT (78mg, 0.58 mmol), EDCI (III mg, 0.58 mmol), DIEA (137 μL, 0.77 mmol) and2-amino-1-phenylethanol (52 mg, 0.38 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and dissolved in methylene chloride (2 mL). Themethylene chloride solution was quenched with brine, dried over MgSO₄,filtered, and the solvent was removed in vacuo to give2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-N-(2-hydroxy-2-phenyl-ethyl)-propionamide9a as a yellow oil. The yellow oil was dissolved in methylene chloride(1 mL), and Dess Martin reagent (162 mg,0.38 mmol) was added. Themixture was stirred overnight and quenched with 1N NaOH aqueous solutionand brine. The organic solution was concentrated to dryness and purifiedby flash column chromatography (NH₄OH:MeOH:CH₂Cl₂, 1:5:94) to givecompound 9b, 70% yield. (MH⁺=377.2). A solution of compound 9b (68 mg,0.18 mmol) in POCl₃ (1 mL) was heated at 125° C. under nitrogen for 2 h.The reaction mixture was cooled, poured over ice, and rendered basic topH 7-8 using concentrated NH₄OH. To the ice-cold aqueous layer was addedbrine (2 mL) and the mixture was extracted with methylene chloride (3×1mL). The organic layers were combined, dried over MgSO₄ and filtered,and the solvent was removed in vacuo to give a dark oil which waspurified by prep HPLC to givedimethyl-(2-{3-[1-(5-phenyl-oxazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine9-1 as the TFA salt, 13% yield. (MH⁺=359.2)

Example 10DIMETHYL-(2-{3-[1-(5-PHENYL-THIAZOL-2-yl]-ETHYL]-1H-INDEN-2-yl}-ETHYL)-AMINE

A solution of compound 9b (27 mg, 0.07 mmol) and Lawesson's reagent (113mg, 0.28 mmol) in toluene (0.5 mL) was refluxed for 4 hours undernitrogen. The reaction mixture was cooled and solvent removed in vacuoto give a yellow residue which was purified by preparative HPLC to givedimethyl-(2-{3-[1-(5-phenyl-thiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine10-1 as the TFA salt, 15% yield. (MH⁺=375.1)

In a similar mannerdimethyl-(2-{3-[1-(5-methyl-thiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine10-2 was prepared from compound 11b. (MH⁺=313)

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 10-1 5-phenyl-thiazol-2-yl 374.55 375.15.971 10-2 5-methyl-thiazol-2-yl 312.48 313.0 4.570

Example 11DIMETHYL-(2-{3-[1-(5-METHYL-OXAZOL-2-YL)-ETHYL]-1H-INDEN-2-yl}-ETHYL)-AMINE

To a solution of compound 7-2 (0.2 g, 0.77 mmol) in THF (2 mL) was addedHOBT (0.158 g, 1.16 mmol), EDCI (0.22 g, 1.16 mmol), DIEA (0.27 mL, 1.54mmol) and DL-1-amino-2-propanol (60 μL, 0.8 mmol). The reaction mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and purified by flash column chromatography(NH₄OH:MeOH:CH₂Cl₂, 11:5:94) to give compound 11a, 94% yield.(MH⁺=317.2). Compound 11a (70 mg, 0.22 mmol) was dissolved in methylenechloride (1 mL), and Dess Martin reagent (154 mg, 0.38 mmol) was added.The reaction mixture was stirred overnight and quenched with 1N NaOHaqueous solution and brine. The organic solution was concentrated todryness and purified by flash column chromatography (NH₄OH:MeOH:CH₂Cl₂,1:5:94) to afford compound 11b, 30% yield. (MH⁺=315.2). A solution of11b (32 mg, 0.1 mmol) in POCl₃ (0.5 mL) was heated at 125° C. undernitrogen for 2 h. The reaction mixture was cooled, poured onto ice, andrendered basic to pH 7-8 using concentrated NH₄OH. To the ice-coldaqueous layer was added 1 mL of brine, and the mixture was extractedwith methylene chloride (3×0.5 mL). The organic layers were combined,dried over MgSO₄ and filtered, and the solvent was removed in vacuo togive a dark oil which was purified by preparative HPLC to afford the TFAsalt of compound 11-1, 39% yield. (MH⁺=297.1)

Example 12DIMETHYL-(2-{3-[1-(5-METHYL-4,5-DIHYDRO-OXAZOL-2-YL)-ETHYL]-1H-INDEN-2-YL}-ETHYL)-AMINE

To a solution of 11a (0.1 g, 0.33 mmol) in methylene chloride (2 mL) andDIEA (115 μL, 0.66 mmol), MsCl (39 μL, 0.50 mmol) was added at 0° C.with stirring. The reaction mixture was stirred overnight andconcentrated to dryness in vacuo. The residue 12a was dissolved inmethanol (2 mL) and 1N NaOH aqueous solution (0.5 mL) was added. Themixture was stirred overnight at room temperature and concentrated to ayellow oil. The yellow oil was purified by flash column chromatography(NH₄OH:MeOH:CH₂Cl₂, 1:5:94) to afforddimethyl-(2-{3-[1-(5-methyl-4,5-dihydro-oxazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine12-1, 69% yield. (MH⁺=299.1)

Example 13(2-{3-[1-(4,5-DIHYDRO-OXAZOL-2-YL)-ETHYL]-1H-INDEN-2-yl}-ETHYL)-DIMETHYL-AMINE

To a solution of 7-2 (0.2 g, 0.77 mmol) in THF (2 mL) was added HOBT(0.158 g, 1.16 mmol), EDCI (0.22 g, 1.16 mmol,) DIEA (27 μL, 1.54 mmol)and ethanolamine (49 μL, 0.8 mmol). The reaction mixture was stirred atroom temperature overnight, concentrated in vacuo and purified by flashcolumn chromatography (NH₄OH:MeOH:CH₂C₂, 1:5:94) to afford compound 13a,94% yield. (MH⁺=303.2). To a solution of 13a (100 mg, 0.33 mmol) inmethylene chloride (2 mL) and DIEA (118 μL, 0.66 mmol), MsCl (40 μL,0.50 mmol) was added at 0° C. with stirring. The reaction mixture wasstirred overnight and concentrated to dryness in vacuo. The mesylcompound 13b was dissolved in methanol (2 mL) and 1N NaOH aqueoussolution (0.5 mL) was added. The mixture was stirred overnight at roomtemperature and concentrated to a yellow oil. The yellow oil waspurified by flash column chromatography (NH₄OH:MeOH:CH₂Cl₂, 1:5:94) toafford(2-{3-[1-(4,5-dihydro-oxazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-dimethyl-amine13-1, 71% yield. (MH⁺=285.1)

Example 14DIMETHYL-(2-{3-[1-(5-METHYL-[1,3,4]THIADIAZOL-2-YL)-ETHYL]-1H-INDEN-2-yl}-ETHYL)-AMINE

To a solution of 7-2 (0.1 g, 0.38 mmol) in dichloromethane (10 mL),acetic acid hydrazide (72 mg, 0.965 mmol), EDCI (0.111 g, 0.58 mmol),HOBT (79 mg, 0.59 mmol) and DIEA (134 μL, 0.77 mmol) were added. Thereaction mixture was stirred at room temperature overnight. Additionaldichloromethane was added and the mixture was washed with water. Theorganic layer was dried and concentrated in vacuo to give 14a. Theresidue was dissolved in toluene (1 mL) and Lawesson's reagent (0.32 g,0.78 mmol) was added. The mixture was refluxed overnight at roomtemperature.

After addition of 3N HCl the reaction mixture was washed with diethylether. The aqueous solution was neutralized with NH₄OH and extractedwith dichloromethane. The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo to give 20 mg ofdimethyl-(2-{3-[1-(5-methyl-[1,3,4]thiadiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine14-1 (17% yield). (MH⁺=314).

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 14-1 5-methyl-[1,3,4]thiadiazol-2-yl313.47 314 3.654 14-2 5-phenyl-[1,3,4]thiadiazol-2-yl 375.54 376 5.173

Example 15 METHYL-{2-[3-(1-PYRAZIN-2-YL-ETHYL)-1H-INDEN-2-YL]-ETHYL}-AMINE

To a solution ofdimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine 4-1(180 mg, 0.61 mmol) in dichloroethane, α-chloroethylformate (86 μL, 0.76mmol) was added at 0° C. After stirring for 15 min at rt and 50 min at90° C., the mixture was concentrated in vacuo, taken up indichloromethane, washed with water (2×), HCl (1N), water, dried (Na₂SO₄)and concentrated in vacuo. The residue was dissolved in MeOH and heatedat 90° C. for 2 hrs in a sealed tube, concentrated in vacuo and purifiedby silica gel column chromatography (dichloromethane/MeOH=98/2 up to92/8) to afford 15-1 (12% yield). (MH+=280).The enantiomers wereseparated using chiralcel OD-H column chromatography (profile 9) to givemethyl-{2-[3-((R)-1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine 15-2and methyl-{2-[3-((S)-1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine15-3. Alternatively, instead of dissolving the residue in MeOH, theresidue may be taken up in 1N HCl (5 mL), stirred at 40° C. for 30 min,concentrated and purified by preparative HPLC to afford 15-6. (MH⁺=299,t_(R)=4.436 min (2)

The following compounds were made according to this procedure:

No. R₁ R_(2b) R₃ MW MH⁺ t_(R) (method) 15-1 Pyrazin-2-yl —CH₃ H 279.38280 3.82 15-2 Pyrazin-2-yl (R)-CH₃ H 279.38 280 3.699 profile 9 15-3Pyrazin-2-yl (S)-CH₃ H 279.38 280 3.767 profile 9 15-4 Pyrazin-2-yl H H265.36 266 3.380 15-5 Pyrazin-2-yl CH₃ CH₃ 293.41 294 4.379 15-64-methyl- CH₃ H 298.45 299 4.436 thiazol-2-yl

Example 16ETHYL-METHYL-[2-(3-PYRAZIN-2-YL-METHYL-1H-INDEN-2-YL)-ETHEYL]-AMINE

To a solution ofmethyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine 15-4 (0.052mmol, 15 mg) dissolved in dimethylacetmamide (400 μL), acetaldehyde (20μL, 0.36 mmol) and sodium triacetoxyborohydride (18 mg, 0.085 mmol) wereadded. The mixture was stirred overnight at rt, diluted with MeOH, andpurified by preparative HPLC to afford 9 mg ofethyl-methyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine 16-1.(MH⁺=293.9)

The following compounds were made according to this procedure:

No. R₁ MW MH⁺ t_(R) (method 2) 16-1 —CH₂CH₃ 293.41 293.9 3.700 16-2—CH₂CH₂CH₃ 307.44 307.9 4.041 16-3 —CH₂CH₂OH 309.41 310.1 3.377

Example 17(2-FLUORO-ETHYL)-METHYL-[2-(3-PYRAZIN-2-ylmethyl-1H-INDEN-2-YL)-ETHYL]-AMINE

To a solution ofmethyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine 15-1 (37 mg,0.14 mmol) dissolved in acetone (400 μL), potassium carbonate (31 mg,0.22 mmol) and 1-bromo-2-fluoro-ethane (9 μL, 0.13 mmol) were added. Themixture was refluxed for 3 hours, additional 1-bromo-2-fluoro-ethane (20μL, 0.27 mmol) was added and refluxing was continued for 5 hours. Themixture was filtered, concentrated in vacuo, dissolved in MeOH andpurified by preparative HPLC to afford 12 mg of(2-fluoro-ethyl)-methyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine17-1. (MH⁺=312.2)

Example 18DIMETHYL-[1-METHYL-2-(3-PYRAZIN-2-YLMETHYL-1H-INDEN-2-YL)-ETHYL]-AMINE

1-Indanone (7.92 g, 60 mmol) dissolved in THF (20 mL) was added dropwiseto a solution of LDA (30 mL, 2N solution in heptanes/THF/ethylbenzene,60 mmol) in THF (200 mL) at −78° C. After stirring at −78° C. for 1 h,chloroacetone (5 mL, 5.8 g, 63 mmol) in THF (20 mL) was added dropwise.The resultant mixture was warmed to rt overnight. The reaction mixturewas quenched with saturated NH₄Cl (50 mL) and water (50 mL). The organiclayer was separated and the aqueous solution was extracted with EtOAc(200 mL). The combined organic layers were dried (Na₂SO₄), concentratedin vacuo and purified by flash chromatography(eluent:hexanes/EtOAc=10/1) to gave 2-(2-oxo-propyl)-indan-1-one 18a(9.8 g, 86% yield).

Dimethylamine (3 mL, 2M solution in THF, 6 mmol) was added to a solutionof (2-oxo-propyl)-indan-1-one 18a (1.128 g, 6 mmol) in DMA (10 mL) andHOAc (0.1 mL). After stirring for 0.5 hr at rt, NaBH(OAc)₃ (1.4 g, 6.6mmol) was added. After 24 hours, the mixture was diluted with EtOAc and1N HCl. The acid layer was separated, neutralized with NH₄OH andextracted with EtOAc. The combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo to give2-(2-dimethylamino-propyl)-indan-1-one 18b which was used for the nextstep without further purification.

To a solution of LDA (1 mL, 2M solution, 2 mmol) in THF (5 mL) at 0° C.,methylpyrazine (0.2 mL, 104 mg, 2.2 mmol) was added dropwise. Afterstirring at 0° C. for 0.5 h, 2-(2-dimethylamino-propyl)-indan-1-one 18b(109 mg, 0.5 mmol) in THF (2 mL) was added dropwise. The mixture wasstirred at rt overnight. A small piece of ice was added to quench thereaction. The mixture was extracted with Et₂O, washed with NaHCO₃aqueous solution, then extracted with 20% HCl (2×5 mL). The combined HCllayers were heated to 100° C. for 1 hour. After cooling to roomtemperature, the mixture was neutralized with cooled NH₄OH and extractedwith EtOAc. The organic layer was dried over Na₂SO₄ and concentrated invacuo. Purification by HPLC gavedimethyl-[1-methyl-2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine18-1 as the TFA salt. (MH⁺=293.9).

Separation by chiral HPLC (profile 8) afforded the (S) and (R)enantiomers, compounds 18-2 and 18-3, respectively.

The following compounds were made according to this procedure:

No. R₁ R —NR_(5a)R_(5b) MW MH⁺ t_(R)(method 2) 18-1 Pyrazin- CH₃—N(CH₃)₂ 293.41 293.9 3.652 2-yl 18-2 Pyrazin (S)-CH₃ —N(CH₃)₂ 293.41293.9 3.636 2-yl profile 8 18-3 Pyrazin (R)-CH₃ —N(CH₃)₂ 293.41 293.93.640 2-yl profile 8 18-4 Pyrazin- CH₃ Pyrrolidin- 319.45 319.9 3.9692-yl 1-yl 18-5 Pyrida- CH₃ Pyrrolidin- 319.45 319.9 3.646 zin-3-yl 1-yl

Example 193-[5-FLUORO-2-(2-PYRROLIDIN-1-YL-ETHYL)-3H-INDEN-1-YLMETHYL]-PYRIDAZINE

A mixture of 5-fluoro-1-indanone (15 g, 100 mmol), glyoxylic acid (40%in H₂O, 37 g, 200 mmol) and sulfuric acid (98%, 5 mL) in dioxane (100mL) was refluxed for 5 hrs. After cooling to room temperature, theprecipitated solid was filtered and washed with water (20 mL). Thefiltrate was concentrated in vacuo to generate a solid which was washedwith H₂O (100 mL). The combined solids were dissolved in acetic acid(200 mL) then water (80 mL) and zinc dust (7.8 g, 120 mmol) were added.The resultant mixture was stirred at 100° C. for 1 hour and allowed tocool down to room temperature. The excess zinc was filtered off. Waterwas added to the filtrate and the mixture was extracted with Et₂O (2×200mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated to give (5-fluoro-1-oxo-indan-2-yl)-acetic acid 19a as anoil which solidified upon standing.

Similarly (5-methoxy-1-oxo-indan-2-yl)-acetic acid 19a.1 (MH⁺=220.9) and(1-oxo-indan-2-yl)-acetic acid 19a.2 (MH⁺=190.9) were prepared.

To a solution of LDA (40 mL, 80 mmol, 2N solution) in THF (400 mL) at 0°C., 3-methylpyridazine (8.5 g, 90 mmol) was added dropwise. Afterstirring for 15 min at 0° C., a solution of(5-fluoro-1-oxo-indan-2-yl)-acetic acid 19a (4.16 g, 20 mmol) in THF(100 mL) was added dropwise. The resultant mixture was stirred for 2hours at 0° C. and subsequently quenched with NH₄OH (4 mL). The reactionmixture was extracted with 5% NH₄OH (3×20 mL). The combined aqueousextractions were washed with EtOAc (50 mL) and then concentrated to givean oil which was dissolved in 20% HCl (20 mL) and heated to 95° C. for 1hour. After addition of HOAc (10 mL) the mixture was cooled to roomtemperature. HOAc was removed under vacuum. The residue was dissolved inwater (150 mL) and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (150 mL), dried over Na₂SO₄ andconcentrated to give(6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-acetic acid 19b as anoil which was used without further purification.

To a solution of (6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-aceticacid 19b (100 mg, 0.35 mmol) in DMF(5 mL), HOBt (71 mg, 0.52 mmol), EDCI(73 mg, 0.38 mmol) and pyrrolidine (60 μL, 0.7 mmol) were added. Themixture was stirred overnight and EtOAc (50 mL) was added. The mixturewas washed with 1N HCl (20 mL), 1N NaOH (20 mL) and brine, dried(Na₂SO₄) and concentrated in vacuo to give a residue which was thendissolved in THF (5 mL) and added to a solution of LiAlH₄ (1 mmol in 10mL THF). The resultant mixture was refluxed for 2 hours. Once cooled tort, the mixture was dissolved in EtOAc and washed with 1N NaOH. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuofollowed by preparative HPLC purification to give3-[5-fluoro-2-(2-pyrrolidin-1-yl-ethyl)-3H-inden-1-ylmethyl]-pyridazine19-1. (MH⁺=324.1)

The following compounds were made according to this procedure:

No. —NR_(5a)R_(5b) MW MH⁺ t_(R) (method 2) 19-1 Pyrrolidin-1-yl 323.41324.1 3.616 19-2 Morpholin-4-yl 339.41 340.0 3.467 19-33-(R)-hydroxy-pyrrolidin-1-yl 339.41 340.1 3.413 19-43-(S)-hydroxy-pyrrolidin-1-yl 391.41 340.1 3.449

Example 203-[2-(2-AZETIDIN-1-YL-ETHYL)-5-FLUORO-3H-INDEN-1-YLMETHYL]-PYRIDAZINE

A solution of (5-fluoro-1-oxo-indan-2-yl)-acetic acid 19a (8.5 g, 41mmol) in THF (100 mL) was added dropwise to a solution of LiAlH₄ (7.6 g,200 mmol) in THF (200 mL) at 0° C. After stirring at 0° C. for 15 min,the reaction mixture was refluxed for 1 hour. The reaction mixture wascooled to room temperature and carefully quenched by the sequentialaddition of H₂O, 15% NaOH and H₂O. The mixture was stirred for half anhour, and the solid was filtered off using a celite pad and washed withexcess THF. The combined filtrates were dried over Na₂SO₄ andconcentrated to afford 5-fluoro-2-(2-hydroxy-ethyl)-indan-1-ol as awhite solid (7.67 g, 95% yield, 38 mmol), which was dissolved indichloromethane (160 mL). Triethylamine (10 mL, 70 mmol),4-dimethylaminopyridine (484 mg, 3.9 mmol) and t-butyldimethylsilylchloride (6.47 g, 43 mmol) were added sequentially. After stirring for 2hrs at room temperature, the reaction mixture was cooled to 0° C. andquenched with saturated NH₄Cl. The organic layer was separated and theaqueous layer was extracted with dichloromethane. The combined organiclayers were dried over Na₂SO₄, concentrated and purified by flashchromatography to generate2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-fluoro-indan-1-ol. Asolution of this alcohol (3.1 g, 10 mmol) in dichloromethane (50 mL) wasadded to a solution of Dess-Martin periodinane (5 g, 11.6 mmol) indichloromethane (100 mL). After stirring at room temperature for 20 min,Et₂O (500 mL) was added followed by 1.3M NaOH (100 mL). The Et₂O layerwas separated, washed with 1.3 M NaOH (100 mL) and water (200 mL), driedover Na₂SO₄, concentrated and purified by flash chromatography(hexanes/EtOAc=20/1) to give2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-fluoro-indan-1-one 20a asa colorless oil (2.04 g, 66% yield).

To a solution of LDA (3 mL, 6 mmol) in THF (40 mL) at 0° C.,3-methylpyridazine (658 mg, 7 mmol) was added dropwise. After stirringat 0° C. for 0.5 hr,2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-fluoro-indan-1-one 20a(616 mg, 2 mmol) in THF (5 mL) was added dropwise. After stirring at 0°C. for 2 hours, the reaction was quenched with cold water (50 mL). Theorganic layer was separated and the aqueous solution was extracted withEtOAc (50 mL). The combined organic layers were washed with brine,concentrated and the residue was dissolved in 20% HCl (5 mL). Themixture was stirred overnight then made basic with NaOH and extractedwith EtOAc. The organic extractions were washed with brine, dried overNa₂SO₄, concentrated and purified by flash chromatography (EtOAc up toEtOAc/MeOH=95/5) to give 216 mg of2-(6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethanol 20b (40%yield).

To a solution of2-(6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethanol 20b (27 mg,0.1 mmol) in dichloromethane (5 mL), DIEA (0.03 mL, 26 mg, 0.2 mmol) andMsCl (0.15 mmol) were added. The resultant mixture was stirred at roomtemperature overnight. Saturated NaHCO₃ (2 mL) was added to quench thereaction. The mixture was partition end between H₂O (15 mL) anddichloromethane (15 mL). The organic layer was separated, dried overNa₂SO₄ and concentrated to give 20c as a black oil, which was dissolvedin iPrOH (2 mL). DIEA (0.3 mmol) and azetidine (0.2 mmol) were added andthe mixture was heated at 80° C. overnight, concentrated and purified bypreparative HPLC to afford3-[2-(2-azetidin-1-yl-ethyl)-5-fluoro-3H-inden-1-ylmethyl]-pyridazine20-1 in 80% yield.

Example 212-{1-[2-(2-AZETIDIN-1-YL-ETHYL-5-METHOXY-3H-INDEN-1-YL]-ETHYL}-PYRARAZINE

A mixture of(5-methoxy-1-oxo-indan-2-yl)-acetic acid 19a.1 (1 g,4.5mmol), EDCI (949 mg, 5 mmol), HOBt (1.5 g, 11.3 mmol) and DIEA (1.7 mL,9 mmol) in 20 mL dichloromethane was stirred at room temperature for 30min. Pyrrolidine (483 mg, 6.8 mmol) was added and the resulting reactionmixture was stirred at room temperature for 2 hr. Water was added andthe organic layer separated, dried over MgSO₄, filtered and concentratedto afford 5-methoxy-2-(2-oxo-2-pyrrolidin-1-yl-ethyl)-indan-1-one 21a in61% yield. (MH⁺=274)

A solution of 5-methoxy-2-(2-oxo-2-pyrrolidin-1-yl-ethyl)-indan-1-one21a (700 mg, 2.56 mmol) in 5 mL of THF and 2 mL of dichloromethane wasadded dropwise to a mixture of LiAlH₄ (150 mg, 3.9 mmol) in 5 mL THF at0° C. The resulting reaction mixture was stirred for 20 min and thenrefluxed for 3 hrs. The reaction mixture was cooled to room temperatureand carefully quenched by the sequential addition of H₂O, 15% NaOH andH₂O. The mixture was stirred for half an hour, and the solid wasfiltered off using a celite pad and washed with excess THF. The combinedfiltrates were dried over MgSO₄ and concentrated to afford5-methoxy-2-(2-pyrrolidin-1-yl-ethyl)-indan-1-ol 21b as a white solid(421 mg, 63% yield). (MH⁺=262.1)

A mixture of 5-methoxy-2-(2-pyrrolidin-1-yl-ethyl)-indan-1-ol 21b (400mg, 1.5 mmol), diphenylmethanone (1.4 g, 1.5 mmol) and KOtBu (421 mg,3.8 mmol) in toluene (10 mL) was heated at 120° C. under N₂ atmospherefor 3 hrs. The cooled mixture was poured into ice (10 g) and extractedwith 10% HCl until the HCl solution was colorless. The combined acidextracts were washed with EtOAc and added dropwise with stirring into28% NH₄OH (10 mL) and ice. This basic solution was extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine, driedover MgSO₄ and concentrated to give5-methoxy-2-(2-pyrrolidin-1-yl-ethyl)-indan-1-one 21c as an oil (240mg,62% yield). (MH⁺=260)

Alternatively the oxidation from the substituted indan-1-ol to thesubstituted indan-1-one may use chromium (VI) oxide as reagent. -Amixture of pyridine (1.5 mL) and dichloromethane (25 mL) was stirred at0° C. for 15 min. Chromium (VI) oxide (900 mg, 9 mmol) was added and themixture was stirred for an additional 15 min at 0° C., allowed to warmto room temperature and stirred for an additional hour at roomtemperature. A solution of2-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethyl]-indan-1-ol (405 mg, 1.5 mmol)was added and stirring continued for 15 min. After decanting, thedichloromethane layer was washed with water and dried over MgSO₄. Uponconcentration 301 mg of the2-[2-(3,3-difluoro-pyrrolidin-1-yl)-ethyl]-indan-1-one was obtained asan oil (76%) and used in the next step without further purification.(MH⁺=266)

A solution of 2-ethylpyrazine (100 mg, 0.9 mmol) in THF (2 mL) was addeddropwise to a mixture of LDA (0.41 mL, 0.82 mmol, 2M) in THF (3 mL) at0° C. A solution of 5-methoxy-2-(2-pyrrolidin-1-yl-ethyl)-indan-1-one21c (100 mg, 0.41 mmol) in THF (2 mL) was added dropwise and theresulting mixture was stirred at 0° C. for 1 hr. Water (10 mL) was addedto quench the reaction followed by EtOAc (10 mL) and NH₄OH (10 mL). Theorganic layer was separated and the aqueous layer was extracted withEtOAc (3×3 mL). The combined organic layers were concentrated and theresidue was dissolved in 4 mL of 20% HCl and the resulting mixture wasstirred at room temperature for 2 hours. The mixture was then pouredonto 10 g of ice and 4 mL of NH₄OH was added dropwise. The resultingmixture was stirred and allowed to warm to room temperature. The organiclayer was separated and the aqueous layer was extracted with EtOAc (3×).The combined organic layers were dried over MgSO₄ and concentrated.Preparative HPLC chromatography afforded2-{1-[2-(2-azetidin-1-yl-ethyl)-5-methoxy-3H-inden-1-yl]-ethyl}-pyrazine21-1. (MH⁺=336.1)

The following compounds were made according to this procedure:

No R₃ R₁ NR_(5a)R_(5b) R_(2b) MW MH⁺ t_(R) (method 2) 21-1 OCH₃Pyrazin-2-yl Azetidin-1-yl CH₃ 335.45 336.1 3.947 21-2 OCH₃ Pyrazin-2-ylAzetidin-1-yl (R)CH₃ 335.45 336.1 3.941 Profile 7 21-3 OCH₃ Pyrazin-2-ylAzetidin-1-yl (S)_CH₃ 335.45 336.1 3.974 Profile 7 21-4 OCH₃Pyrazin-2-yl Pyrrolidin-1-yl CH₃ 349.48 350.1 4.960 21-5 OCH₃Pyrazin-2-yl Pyrrolidin-1-yl H 335.45 336.1 3.749 21-6 OCH₃Pyridazin-3-yl Pyrrolidin-1-yl H 335.45 336.1 3.500 21-7 H Pyrazin-2-ylPyrrolidin-1-yl H 305.42 306.1 3.673 21-8 H Pyridazin-3-ylPyrrolidin-1-yl H 305.42 306.1 3.473 21-9 OCH₃ Pyrazin-2-ylMorpholin-4-yl H 351.45 352.1 3.610 21-10 H Pyrazin-2-yl Azetidin-1-yl H291.40 292.1 3.585 21-11 H Pyrazin-2-yl 3,3-Difluoro- H 309.4 310 3.605pyrrolidin-1-yl 21-12 H Pyrazin-2-yl 3-Fluoro- H 341.1 342.1 3.868azetidin-1-yl

Example 22DIMETHYL-(2-{3-[1-(4-METHYL-THIAZOL-2-YL)-ETHYL]-1H-INDEN-2-YL}-ETHYL-AMINE

To a solution of [2-(1H-inden-2-yl)-ethyl]-dimethyl-amine 3a (2 g, 10.68mmol) in anhydrous THF (40 mL) cooled to −78° C., nBuLi (12.8 mmol, 8mL, 1.6M) was added. After stirring at −78° C. for 1 hr,2-bromoproprionitrile (10.68 mmol, 0.92 mL) in THF (10 mL) was added.The reaction was mixture warmed to reach room temperature while beingstirred overnight. The mixture was concentrated in vacuo.Dichloromethane was added, and the mixture was washed with 1N NaOH andwater, dried over MgSO₄, filtered and concentrated in vacuo to afford2.08 g of 2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-propionitrile 22awhich was used in the next step without further purification (83%yield). (MH⁺=241, t_(R)=3.675 (2))

To a solution of 2-[2-(2-dimethylamino-ethyl)-3H-inden1-yl]-propionitrile 22a (2 g, 8.33 mmol) in ethylacetate (70 mL),dithiophosphoric acid O,O-diethylester (1.55 g,8.33 mmol) in EtOAc (10mL) was added. HCl was bubbled through the reaction mixture whilestirring. After the internal temperature had stabilized, the reactionwas sealed and stirred for 3 days. An additional portion ofdithiophosphoric acid O,O-diethylester (6.1 mmol, 1 mL) was added andHCl gas was bubbled through while being stirred overnight. The mixturewas concentrated in vacuo, diluted with dichloromethane, washed withwater, dried (MgSO₄), filtered and concentrated in vacuo. Silica gelcolumn chromatography (gradient of dichloromethane/MeOH/NH₄OH 99/1/0.2to dichloromethane/MeOH/NH₄OH 98/2/0.2) afforded 0.72 g of2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-thiopropionamide 22b (31%yield).

To a solution of2-[2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-thiopropionamide 22b (0.372g, 1.36 mmol) in EtOH (10 mL), chloroacetone (0.22 mL, 2.72 mmol) wasadded. The mixture was stirred at 80° C. overnight. The reaction mixturewas concentrated in vacuo and the residue was purified using silica gelcolumn chromatography. (dichloromethane/MeOH/NH₄OH 98/2/0.02 as elutant)to afford 0.174 g ofdimethyl-(2-{3-[1-(4-methyl-thiazol-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-amine22-1 in 41% yield. (MH⁺=313) Separation by chiral HPLC (Chiralpak-AD-H,profile 6) afforded the R and S enantiomers 22-2 and 22-3.

The following compounds were made according to this procedure:

No R₃ R_(2b) Method MH⁺ t_(R) (method 2) 22-1 H —CH₃ 312.48 313 4.36322-2 H —(R)—CH₃ 312.48 313 4.929 profile 6 22-3 H —(S)—CH₃ 312.48 3134.875 profile 6 22-4 OCH₃ —CH₃ 342.50 342.9 4.478 22-5 Cl —(R)—CH₃346.92 346.8 5.345 profile 6

Example 23

To a cooled (0° C.) solution of propionitrile (0.78 mL, 10.94 mmol) inTHF (5 mL), LDA (5.4 mL, 10.94 mmol, 2M) was added. After 30 min at 0°C. a solution of 5-chloro-2-(2-dimethylamino-ethyl)-indan-1-one 2d (0.65g, 2.73 mmol) in THF (5 mL) was added. After stirring for 30 min, waterwas added followed by extraction with EtOAc. The combined organic layerswere washed with water, dried (MgSO₄) and concentrated in vacuo. 10% HCl(10 mL) was added to the residue and the mixture was stirred at roomtemperature. The solvent was removed in vacuo and purification by silicagel column chromatography (dichloromethane/MeOH (NH₄OH)=98/2 (0.2%) withgradient up to dichloromethane/MeOH (NH₄OH)=95/5 (0.2%)) afforded 0.27 gof 2-[5-chloro-2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-propionitrile23-1. (MH⁺=274.8)

To a solution of2-[5-chloro-2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-propionitrile 23-1(0.27 g, 1 mmol) in DMA (2 mL), isopropylamine (42 μL) was added. H₂Swas bubbled into the reaction mixture which was stirred overnight at 30°C. After preparative HPLC, 0.1 g of2-[5-chloro-2-(2-dimethylamino-ethyl)-3H-inden-1-yl]-thiopropionamide23a was isolated.

To a solution 23a in a mixture of EtOH (1 mL) and acetone (1 mL),2-bromo-1,1-diethoxy-ethane (78 μL, 0.52 mmol) was added along with 2drops of conc. sulfuric acid. The mixture was stirred overnight at 80°C. and purified by preparative HPLC to generate{2-[6-chloro-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine(52 mg). Both the R and S enantiomers, 23-2 and 23-3 were isolated afterchiral HPLC separation.

The following compounds were made according to this procedure:

No. R₁ R_(2b) MW MH⁺ t_(R) (method 2) 23-1 —CN —CH₃ 274.79 274.8 4.58723-2 Thiazol-2-yl —(R)—CH₃ 332.90 332.8 4.930 profile 6 23-3Thiazol-2-yl —(S)—CH₃ 332.90 332.8 4.910 profile 6

Example 24 2-(2-DIMETHYLAMINO-ETHYL)-1-PYRAZIN-2-YLMETHYL-3H-INDEN-5-OL

A solution of[2-(6-methoxy-3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine4-40 (0.5 g, 1.61 mmol) in CHCl₃ (8 mL) was added dropwise to a solutionof BBr₃ (3.1 mL, 32.3 mmol) in CHCl₃ (3 mL) at rt. The resultingreaction mixture was stirred at rt for 2.5 hrs. The reaction mixture wasquenched with 50 mL of dilute NH₄OH (ice cold) and then stirred at 0° C.for 15 min. The layers were separated and the organic phase wasextracted with 40 mL of 1 M NaOH. The aqueous layers were combined andthen concentrated to about 25 mL. The pH of the concentrate was adjustedto ˜10 with NaOH. The solution was saturated with NaCl and thenextracted with dichloromethane (4×12 mL). The combined organic layerswere dried (MgSO₄), filtered and concentrated in vacuo to give a darkbrown oil (418 mg), which was purified by preparative HPLC to afford theTFA salt of 2-(2-dimethylamino-ethyl)-1-pyrazin-2-ylmethyl-3H-inden-5-ol24-1 (378 mg).

Example 25{2-[5-METHOXY-3-(1-THIAZOL-2-YL-ETHYL)-1H-INDEN-2-yl]-ENTHYL}-DIMETHYLAMINE

To a solution of 3b (0.148 g, 0.68 mmol) in THF (2 mL) at −78° C.,n-Butyllithium (0.44 mL, 0.71 mmol, 1.6M in hexanes) was added. Afterstirring at −78° C. for 1 hour, 2-(1-chloro-ethyl)-thiazole (0.12 mL,0.82 mmol) was added. The resultant mixture was warmed to roomtemperature overnight. Saturated NaHCO₃ (6 mL) and Et₂O (6 mL) wereadded. The organic layer was isolated and dried over Na₂SO₄ andconcentrated to give an oil, which was purified by HPLC to give{2-[5-methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amineand{2-[5-methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amineas TFA salts (20% yield). The enantiomers were separated by chiral HPLC(profile 6) to give 25-1 (3.5 mg, 1.7% yield, MH⁺'329, t_(R)=4.338 min);25-2 (4.0 mg, 1.8% yield, MH⁺=329, t_(R)=4.246 min); 25-3 (3.1 mg, 1.4%yield, MH⁺329, t_(R)=4.325 min; and 25-4 (3.2 mg, 1.4% yield, MH⁺=329,t_(R)=4.310 min).

2-(1-Chloro-ethyl)-thiazole was prepared as follows: To a cooledsolution (0° C.) of 1-thiazol-2-yl-ethanone (10 g, 78.6 mmol) inanhydrous THF (200 mL), LiAlH₄ (3.6 g, 94.4 mmol) was slowly added.After stirring for 30 min, water was added to quench the reaction. THFwas removed under vacuum and dichloromethane was added. The mixture waswashed with 1N NaOH and water and concentrated in vacuo to yield 0.86 gof 1-thiazol-2-yl-ethanol, which was dissolved in dichloromethane (10mL). MsCl (0.52 mL, 6.64 mmol) and DIEA (1.74 mL, 9.96 mmol) were addedand the reaction mixture was stirred overnight at room temperature.Additional aliquots of MsCl (0.52 mL, 6.64 mmol) and DIEA (0.8 mL, 4.55mmol) were added and stirring was continued for 16 hours. Additionalaliquots were added and the mixture stirred overnight. The solvent wasremoved in vacuo and the residue purified through silica gel columnchromatography (eluent: Hexanes/EtOAc=6/1) to give 0.45 g of2-(1-chloro-ethyl)-thiazole.

Example 26 HUMAN HISTAMINE H₁ RECEPTOR BINDING ASSAY

Compounds of the present invention may be evaluated for binding to thehistamine H₁ receptor by a standard binding assay. Crude membranes areprepared from CHO cells transfected with human H₁ receptor expressionconstruct by resuspending cells in lysis buffer (50 mM Tris-HCl pH 7.4,5 mM EDTA, 10 mM MgCl₂ and disrupting under N₂ at a pressure of 900 psi(Parr Cell disruption bomb, cat.4639) for 30 min on ice followed bydifferential centrifugation. The resulting crude membrane pellet isresuspended in assay buffer (50 mM Tris HCl pH 7.4, 100 mM NaCl, 2 mMMgCl₂). Membrane protein concentration is adjusted to 1 mg/ml andaliquots were stored at −80° C. An aliquot of membranes (10-20 μg ofprotein) is incubated for 90 min with 1.5 nM [pyridinyl-5-³H]Pyrilamine(˜30 Ci/mmol, Amersham TRK608) in the presence of varying concentrationsof competing ligand. Non-specific binding is determined in the presenceof excess (1 μM) doxepin. Bound and free ligand are separated by rapidvacuum filtration using a Packard 96-well cell harvester onto UniFilterGF/C filter plates (PerkinElmer) that has been pretreated with 1%polyethyleneimine. The filter plates are then washed with 600 μlphosphate buffered saline containing 0.01% (v/v) Triton-X100. Boundradioligand is determined by scintillation counting using a TopCount-NXT(Packard). Binding data is analyzed by nonlinear, least-squares curvefitting algorithms using GraphPad Prism (GraphPad Software, Inc. SanDiego, Calif.) or ActivityBase (IDBS, Guildford, Surrey, UK). K_(i)values are calculated from IC₅₀ values using the Cheng-Prusoff equation(Biochem. Pharm. 22: 3099-3108, 1973).

Compounds of this invention generally have a K_(i) of less than 10 μM,typically less than 1 μM, and preferably less than 250 nM. The followingcompounds have a K_(i) of 250 nM or less: 4-1, 4-2, 4-3, 4-4, 4-5, 4-6,4-7, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19,4-20, 4-21, 4-22, 4-23, 4-24, 4-25, 4-26, 4-27, 4-28, 4-29, 4-30, 4-32,4-33, 4-34, 4-35, 4-36, 4-37, 4-38, 4-39, 4-40, 4-41, 4-42, 4-43, 4-45,4-46, 4-47 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-9, 5-10, 5-11 6-1, 6-27-1, 7-3 8-1, 8-2 9-1 10-1, 10-2 11-1 12-1 13-1 14-1, 14-2 15-1, 15-2,15-4, 15-5, 15-6 16-1, 16-2, 16-3 17-1 18-1, 18-2, 18-3, 18-4, 18-519-1, 19-2, 19-3, 19-4 20-1 21-1, 21-2, 21-4, 21-5, 21-6, 21-7, 21-8,21-9, 21-10, 21-11, 21-12 22-1, 22-2, 22-3, 22-4, 22-5 23-1, 23-2, 23-325-2, 25-4

Example 27 EEG STUDIES

Adult, male Wistar rats (Charles River Laboratories, 275 g) areanesthetized with inhaled isoflurane and restrained in a stereotaxicdevice. Using aseptic technique, a sterile 6-lead telemetry-basedelectroencephalographic/electromyographic recording unit (TransdomaDataSciences Incorporated) is attached to the rat. Pairs ofelectroencephalographic leads are placed onto the dura in the frontaland occipital cortices. The EMG leads are sutured into nuchaltrapezoidal muscles. An additional lead attached to the muscle layerserves as a ground. Leads are affixed to the skull with dental acrylic.The leads and the attached transmitter are enclosed into a subcutaneouspocket between the scapulae. Rats recover for 7-14 days prior to study.

Rats are individually housed in standard cages with filter top coversand ad libitum food and water in an isolated room with a 24-hour light(12 hours)/dark (12 hours) cycle and controlled humidity. Rats areplaced on their individual telemetry receivers and assess to therecording room is restricted 24 hours prior to the baseline recording.Baseline recordings began 6 hours after lights off, 24 hours prior todosing.

Recordings are made using DataSciences telemetric receivers and compiledwith DataSciences ART-GOLD 2.3 software at a sampling frequency of 100Hz. Recordings from one pair of bilateral EEG leads and from the EMGleads are used to divide the vigilance state of rats into Wake and Sleep(NREM and REM). Power spectra of the EEG signal during individualvigilance states are computed from fast-Fourier transforms generated at512 Hz.

Sedative effects of test compounds are monitored in male Wistar ratsafter oral administration of test compounds and vehicle control (0.25%methylcellulose). Compounds are administered during the activity portionof the diurnal cycle, 6 hours after lights-off.

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

1. A method for treating a condition or disorder, the treatment of whichcan be effected or facilitated by antagonizing a histamine receptor,comprising administering to a patient in need thereof, an effectiveamount of a compound having the following structure:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein: R₁ is R_(1a), R_(1b), —OR, —CN, —C(═O)R, —OC(═O)R or —C(═O)OR,wherein R is alkyl or substituted alkyl; R_(1a) is heterocycle orsubstituted heterocycle, with the proviso that R_(1a) is not pyridinylor substituted pyridinyl; R_(1b) is bicyclic carbocycle or substitutedbicyclic carbocycle; L₁ is a bond or L₂; L₂ is alkanediyl or substitutedalkanediyl; R_(2a) and R_(2b) are the same or different and areindependently hydrogen, alkyl or substituted alkyl; R₃ is, at eachoccurrence, the same or different and independently alkyl, —OR, —SR,—CN, —CF₃ or halogen, wherein R is alkyl or substituted alkyl; R₄ ishydrogen or alkyl; R_(5a) and R_(5b) are the same or different andindependently hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)together with the nitrogen to which they are attached form a heterocycleor substituted heterocycle; and n is 0, 1 or 2 and represents the numberof R₃ groups.
 2. A method for treating insomnia, inducing sleep, orinducing sedation or hypnosis in a patient in need thereof, comprisingadministering to the patient an effective amount of a compound havingthe following structure:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein: R_(1a) is R_(1a), R_(1b), —OR, —CN, —C(═O)R, —OC(═O)R or—C(═O)OR, wherein R is alkyl or substituted alkyl; R_(1a) is heterocycleor substituted heterocycle, with the proviso that R_(1a) is notpyridinyl or substituted pyridinyl; R_(1b) is bicyclic carbocycle orsubstituted bicyclic carbocycle; L₁ is a bond or L₂; L₂ is alkanediyl orsubstituted alkanediyl; R_(2a) and R_(2b) are the same or different andare independently hydrogen, alkyl or substituted alkyl; R₃ is, at eachoccurrence, the same or different and independently alkyl, —OR, —SR,—CN, —CF₃ or halogen, wherein R is alkyl or substituted alkyl; R₄ ishydrogen or alkyl; R_(5a) and R_(5b) are the same or different andindependently hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)together with the nitrogen to which they are attached form a heterocycleor substituted heterocycle; and n is 0, 1 or 2 and represents the numberof R₃ groups.
 3. The method of claim 2 wherein L₁ is a bond and L₂ isethylenediyl.
 4. The method of claim 3 wherein R₄ is hydrogen and R_(5a)and R_(5b) are the same or different and independently alkyl.
 5. Themethod of claim 4 wherein R₁ is R_(1a).
 6. The method of claim 5 whereinR_(1a) is pyrazinyl, substituted pyrazinyl, pyridazinyl or substitutedpyridazinyl.
 7. The method of claim 1 wherein L₁ is a bond and L₂ isethylenediyl.
 8. The method of claim 2 wherein the compound is:[2-(6-fluoro-3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;dimethyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine;[2-(6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;{2-[6-fluoro-3-(3-methoxy-pyrazin-2-ylmethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;[2-(6-chloro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;ordimethyl-[2-(6-methyl-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-amine.9. The method of claim 2 wherein the compound is:dimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;(2-{6-fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-dimethyl-amine;(2-{6-chloro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-dimethyl-amine;{2-[3-(2-methoxy-1-methyl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;dimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;dimethyl-{2-[3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;{2-[6-methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;{2-[6-methoxy-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;dimethyl-{2-[6-methyl-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;or(2-{3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-6-methyl-1H-inden-2-yl}-ethyl)-dimethyl-amine.10. A compound having the following structure:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein: R₁ is R_(1a), R_(1b), —OR, —C(═O)R, —OC(═O)R or —C(═O)OR,wherein R is alkyl or substituted alkyl; R_(1a) is heterocycle orsubstituted heterocycle, with the proviso that R_(1a) is not pyridinylor substituted pyridinyl; R_(1b) is bicyclic carbocycle or substitutedbicyclic carbocycle; L₁ is a bond or L₂; L₂ is alkanediyl or substitutedalkanediyl; R_(2a) and R_(2b) are the same or different and areindependently hydrogen, alkyl or substituted alkyl, with the provisothat when R_(2a) and R_(2b) are both hydrogen, then R₁ is R_(1a) whereinR_(1a) is pyrazinyl, substituted pyrazinyl, pyridazinyl, substitutedpyridazinyl, triazinyl, or substituted triazinyl; R₃ is, at eachoccurrence, the same or different and independently alkyl, —OR, —SR,—CN, —CF₃ or halogen, wherein R is alkyl or substituted alkyl; R₄ ishydrogen or alkyl; R_(5a) and R_(5b) are the same or different andindependently hydrogen, alkyl or substituted alkyl, or R_(5a) and R_(5b)together with the nitrogen to which they are attached form a heterocycleor substituted heterocycle; and n is 0, 1 or 2 and represents the numberof R₃ groups.
 11. The compound of claim 10 wherein R₁ is R_(1a) orR_(1b).
 12. The compound of claim 11 wherein R₁ is R_(1a).
 13. Thecompound of claim 12 wherein L₁ is a bond and L₂ is ethylenediyl. 14.The compound of claim 13 wherein R₄ is hydrogen and R_(5a) and R_(5b)are the same or different and independently alkyl.
 15. The compound ofclaim 14 wherein R_(1a) is pyrazinyl, substituted pyrazinyl, pyridazinylor substituted pyridazinyl.
 16. The compound of claim 15 wherein R_(2a)is hydrogen and R_(2b) is methyl.
 17. The compound of claim 15 whereinR_(2a) and R_(2b) are both hydrogen.
 18. The compound of claim 12wherein R_(1a) is pyrazinyl, substituted pyrazinyl, pyridazinyl orsubstituted pyridazinyl.
 19. The compound of claim 10 wherein R₁ is —OR,—C(═O)R, —OC(═O)R or —C(═O)OR.
 20. The compound of claim 19 wherein L₁is a bond and L₂ is ethylenediyl.
 21. The compound of claim 10 whereinR_(2a) is hydrogen and R_(2b) is alkyl.
 22. The compound of claim 10wherein R_(2a) and R_(2b) are both hydrogen.
 23. The compound of claim10 wherein R_(5a) and R_(5b) are the same or different and independentlyalkyl.
 24. The compound of claim 10 wherein n is
 0. 25. The compound ofclaim 10 wherein n is
 1. 26. The compound of claim 10 wherein R₄ ishydrogen.
 27. The compound of claim 10 wherein R_(5a) and R_(5b)together with the nitrogen to which they are attached form aheterocyclic ring which is optionally substituted with alkyl orsubstituted alkyl.
 28. The compound of claim 21 wherein L₁ is a bond andL₂ is ethylenediyl.
 29. The compound of claim 10, wherein the compoundis:[2-(6-fluoro-3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;dimethyl-[2-(3-pyrazin-2-ylmethyl-1H-inden-2-yl)-ethyl]-amine;[2-(6-fluoro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;{2-[6-fluoro-3-(3-methoxy-pyrazin-2-ylmethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;[2-(6-chloro-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-dimethyl-amine;ordimethyl-[2-(6-methyl-3-pyridazin-3-ylmethyl-1H-inden-2-yl)-ethyl]-amine.30. The compound of claim 8, wherein the compound is:dimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;(2-{6-fluoro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-dimethyl-amine;(2-{6-chloro-3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-1H-inden-2-yl}-ethyl)-dimethyl-amine;{2-[3-(2-methoxy-1-methyl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;dimethyl-{2-[3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;dimethyl-{2-[3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;{2-[6-methoxy-3-(1-thiazol-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;{2-[6-methoxy-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-dimethyl-amine;dimethyl-{2-[6-methyl-3-(1-pyrazin-2-yl-ethyl)-1H-inden-2-yl]-ethyl}-amine;or(2-{3-[1-(3-methoxy-pyrazin-2-yl)-ethyl]-6-methyl-1H-inden-2-yl}-ethyl)-dimethyl-amine.31. A pharmaceutical composition comprising a compound of claim 10 and apharmaceutically acceptable carrier or diluent.
 32. A pharmaceuticalcomposition comprising a compound of claim 29 and a pharmaceuticallyacceptable carrier or diluent.
 33. A pharmaceutical compositioncomprising a compound of claim 30 and a pharmaceutically acceptablecarrier or diluent.